Kinase inhibitors

ABSTRACT

There are provided compounds of formulas III and VIIa: 
     
       
         
         
             
             
         
       
     
     or a salt or protected derivative thereof, wherein Z 2  represents a structural fragment of formula V, 
     
       
         
         
             
             
         
       
     
     wherein R 1A  to R 1E , R 2  to R 4 , R 5a , L and X 1  to X 3  have meanings given in the description, which compounds have antiinflammatory activity, for example through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

FIELD OF THE INVENTION

This invention relates, inter alia, to compounds which areantiinflammatory agents (e.g. through inhibition of one or more ofmembers of: the family of p38 mitogen-activated protein kinase enzymes(referred to herein as p38 MAP kinase inhibitors), for example the alphakinase sub-type thereof; Syk kinase; and the Src family of tyrosinekinases). The invention also relates to the use of such compounds intherapy, including in mono- and combination therapies, especially in thetreatment of inflammatory diseases, including inflammatory diseases ofthe lung (such as asthma and chronic obstructive pulmonary disease(COPD)), eye (such as uveitis or keratoconjunctivitis sicca (dry eyedisease, also known as xerophthalmia)) and gastrointestinal tract (suchas Crohn's disease and ulcerative colitis).

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively) havebeen identified, each displaying different patterns of tissueexpression. The p38 MAPK alpha and beta isoforms are found ubiquitouslythroughout the body, are present in many different cell types and areinhibited by a number of previously described small molecular weightcompounds. Early classes of inhibitors were highly toxic due to thebroad tissue distribution of these isoforms which resulted in off-targeteffects of the compounds. Some of the more recently identifiedinhibitors show improved selectivity for p38 MAPK alpha and betaisoforms and have wider safety margins.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma, COPD and inflammatory bowel disease (IBD). There is nowan abundant literature which demonstrates that p38 MAP kinase isactivated by a range of pro-inflammatory cytokines and that itsactivation results in the recruitment and release of furtherpro-inflammatory cytokines. Indeed, data from some clinical studiesdemonstrate beneficial changes in disease activity in patients duringtreatment with p38 MAP kinase inhibitors. For instance, Smith describesthe inhibitory effect of p38 MAP kinase inhibitors on TNFα (but notIL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006,149:393-404).

The use of inhibitors of p38 MAP kinase in the treatment of COPD and IBDhas also been proposed. Small molecule inhibitors targeted to p38MAPKα/β have proved to be effective in reducing various parameters ofinflammation in:

-   -   cells and tissues obtained from patients with COPD, who are        generally corticosteroid insensitive (Smith, S. J., Br. J.        Pharmacol., 2006, 149:393-404);    -   biopsies from IBD patients (Docena, G. et al., J. Trans.        Immunol., 2010, 162:108-115); and    -   in vivo animal models (Underwood, D. C. et al., Am. J. Physiol.,        2000, 279:L895-902; Nath, P. et al., Eur. J. Pharmacol., 2006,        544:160-167).

Irusen and colleagues also suggested the possibility of involvement ofp38 MAPKα/β on corticosteroid insensitivity via the reduction of bindingaffinity of the glucocorticoid receptor (GR) in nuclei (Irusen, E. etal., J. Allergy Clin. Immunol., 2002, 109:649-657). Clinicalinvestigations in inflammatory diseases with a range of p38 MAP kinaseinhibitors, including AMG548, BIRB 796, VX702, SCIO469 and SCIO323, havebeen described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005,12:2979-2994.). However, the major obstacle hindering the utility of p38MAP kinase inhibitors in the treatment of human chronic inflammatorydiseases has been the toxicity observed in patients. This has beensufficiently severe to result in the withdrawal from clinicaldevelopment of many of the compounds progressed, including all thosespecifically mentioned above.

COPD is a condition in which the underlying inflammation is reported tobe substantially resistant to the anti-inflammatory effects of inhaledcorticosteroids. Consequently, a superior strategy for treating COPDwould be to develop an intervention which has both inherentanti-inflammatory effects and the ability to increase the sensitivity ofthe lung tissues of COPD patients to inhaled corticosteroids. The recentpublication of Mercado et al. (2007; American Thoracic Society AbstractA56) demonstrates that silencing p38 MAPK γ has the potential to restoresensitivity to corticosteroids. Thus, there may be a dual benefit forpatients in the use of a p38 MAP kinase inhibitor for the treatment ofCOPD.

Many patients diagnosed with asthma or with COPD continue to suffer fromuncontrolled symptoms and from exacerbations of their medical conditionthat can result in hospitalisation. This occurs despite the use of themost advanced, currently available treatment regimens, comprising ofcombination products of an inhaled corticosteroid and a long actingβ-agonist. Data accumulated over the last decade indicates that afailure to manage effectively the underlying inflammatory component ofthe disease in the lung is the most likely reason that exacerbationsoccur. Given the established efficacy of corticosteroids asanti-inflammatory agents and, in particular, of inhaled corticosteroidsin the treatment of asthma, these findings have provoked intenseinvestigation. Resulting studies have identified that some environmentalinsults invoke corticosteroid-insensitive inflammatory changes inpatients' lungs. An example is the response arising fromvirally-mediated upper respiratory tract infections (URTI), which haveparticular significance in increasing morbidity associated with asthmaand COPD.

It has been disclosed previously that compounds that inhibit theactivity of both the c-Src and Syk kinases are effective agents againstrhinovirus replication (Charron, C. E. et al., WO 2011/158042) and thatcompounds that inhibit p59-HCK are effective against influenza virusreplication (Charron, C. E. et al., WO 2011/070369). Taken together withinhibition of p38 MAPK, these are particularly attractive properties forcompounds to possess that are intended to treat patients with chronicrespiratory diseases.

Certain p38 MAPK inhibitors have also been described as inhibitors ofreplication of respiratory syncytial virus (Cass L. et al., WO2011/158039).

The precise etiology of IBD is uncertain, but is believed to be governedby genetic and environmental factors that interact to promote anexcessive and poorly controlled mucosal inflammatory response directedagainst components of the luminal microflora. This response is mediatedthrough infiltration of inflammatory neutrophils, dendritic cells andT-cells from the periphery. p38 has become an obvious target forinvestigation in IBD models as a consequence of its ubiquitousexpression in inflammatory cells. Studies investigating the efficacy ofp38 inhibitors in animal models of IBD and human biopsies from IBDpatients indicated that p38 could be a target for the treatment of IBD(Hove, T. ten et al., Gut, 2002, 50:507-512, Docena, G. et al., J.Trans. Immunol, 2010, 162:108-115). However, these findings are notcompletely consistent with other groups reporting no effect with p38inhibitors (Malamut G. et al., Dig. Dis. Sci, 2006, 51:1443-1453). Aclinical study in Crohn's patients using the p38 alpha inhibitor BIRB796demonstrated potential clinical benefit with an improvement inC-reactive protein levels. However this improvement was transient,returning to baseline by week 8 (Schreiber, S. et al., Clin. Gastro.Hepatology, 2006, 4:325-334). A small clinical study investigating theefficacy of CNI-1493, a p38 and Jnk inhibitor, in patients with severeCrohn's disease showed significant improvement in clinical score over 8weeks (Hommes, D. et al. Gastroenterology. 2002 122:7-14).

T cells are known to play a key role in mediating inflammation of thegastrointestinal tract. Pioneering work by Powrie and colleaguesdemonstrated that transfer of naive CD4+ cells into severely compromisedimmunodeficient (SCID) animals results in the development of colitiswhich is dependent on the presence of commensal bacteria (Powrie F. etal. Int Immunol. 1993 5:1461-71). Furthermore, investigation of mucosalmembranes from IBD patients showed an upregulation of CD4+ cells whichwere either Th1 (IFNg/IL-2) or Th2 (IL5/TGFb) biased depending onwhether the patient had Crohn's disease or ulcerative colitis (Fuss I J.et al. J Immunol. 1996 157:1261-70.). Similarly, T cells are known toplay a key role in inflammatory disorders of the eye with severalstudies reporting increased levels of T cell associated cytokines (IL-17and IL-23) in sera of Beçhets patients (Chi W. et al. Invest OphthalmolVis Sci. 2008 49:3058-64). In support of these observations, Direskeneliand colleagues demonstrated that Beçhets patients have increased Th17cells and decreased Treg cells in their peripheral blood (Direskeneli H.et al. J Allergy Clin Immunol. 2011 128:665-6).

One approach to inhibit T cell activation is to target kinases which areinvolved in activation of the T cell receptor signalling complex. Sykand Src family kinases are known to play a key role in this pathway,where Src family kinases, Fyn and Lck, are the first signallingmolecules to be activated downstream of the T cell receptor (Barber E K.et al. PNAS 1989, 86:3277-81). They initiate the tyrosinephosphorylation of the T cell receptor leading to the recruitment of theSyk family kinase, ZAP-70. Animal studies have shown that ZAP-70knockout results in a SCID phenotype (Chan A C. et al. Science. 1994,10; 264(5165):1599-601).

A clinical trial in rheumatoid arthritis patients with the Syk inhibitorFostamatinib demonstrated the potential of Syk as an anti-inflammatorytarget with patients showing improved clinical outcome and reduced serumlevels of IL-6 and MMP-3 (Weinblatt M E. et al. Arthritis Rheum. 200858:3309-18). Syk kinase is widely expressed in cells of thehematopoietic system, most notably in B cells and mature T cells.Through interaction with immunoreceptor tyrosine-based activation motifs(ITAM), it plays an important role in regulating T cell and B cellexpansion as well as mediating immune-receptor signalling ininflammatory cells. Syk activation leads to IL-6 and MMPrelease—inflammatory mediators commonly found upregulated ininflammatory disorders including IBD and rheumatoid arthritis (Wang Y D.et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al.Cytokine. 2006 January 33:106-10).

In addition to playing key roles in cell signalling events which controlthe activity of pro-inflammatory pathways, kinase enzymes are now alsorecognised to regulate the activity of a range of cellular functions,including the maintenance of DNA integrity (Shilo, Y. Nature ReviewsCancer, 2003, 3: 155-168) and co-ordination of the complex processes ofcell division. Indeed, certain kinase inhibitors (the so-called“Olaharski kinases”) have been found to alter the frequency ofmicronucleus formation in vitro (Olaharski, A. J. et al., PLoS Comput.Biol., 2009, 5(7), e1000446; doi: 10.1371/journal.pcbi.1000446).Micronucleus formation is implicated in, or associated with, disruptionof mitotic processes and is therefore undesirable. Inhibition ofglycogen synthase kinase 3α (GSK3α) was found to be a particularlysignificant factor that increases the likelihood of a kinase inhibitorpromoting micronucleus formation. Also, inhibition of the kinase GSK3βwith RNAi has been reported to promote micronucleus formation (Tighe, A.et al., BMC Cell Biology, 2007, 8:34).

Whilst it may be possible to attenuate the adverse effects of inhibitionof Olaharski kinases such as GSK3α by optimisation of the dose and/or bychanging the route of administration of a molecule, it would beadvantageous to identify further therapeutically useful molecules withlow or negligible inhibition of Olaharski kinases, such as GSK 3α and/orhave low or negligible disruption of mitotic processes (e.g. as measuredin a mitosis assay).

Various compounds, including urea derivatives, are disclosed asinhibiting one or more kinases. Examples of such compounds may be foundin WO 99/23091, WO 00/041698, WO 00/043384, WO 00/055139, WO 01/36403,WO 01/4115, WO 02/083628, WO 02/083642, WO 02/092576, WO 02/096876, WO2003/005999, WO 2003/068223, WO 2003/068228, WO 2003/072569, WO2004/014870, WO 2004/113352, WO 2005/005396, WO 2005/018624, WO2005/023761, WO 2005/044825, WO 2006/015775, WO 2006/043090, WO2007/004749, WO 2007/053394, WO 2013/050756, WO 2013/050757, WO2014/027209, WO 2014/033446, WO 2014/033447, WO 2014/033448, WO2014/033449, WO 2014/076484, WO 2014/140582 WO 2014/162121, WO2014/162122, WO 2014/162126 and WO 2015/092423. Further examples may befound in articles published in:

-   Curr. Opin. Drug Devel. (2004, 7(5), 600-616);-   J. Med. Chem. (2007, 50, 4016-4026; 2009, 52, 3881-3891; and 2010,    53, 5639-5655);-   Bioorg. Med. Chem. Lett. (2007, 17, 354-357; 2008, 18, 3251-3255;    2009, 19, 2386-2391; and 2010, 20, 4819-4824);-   Curr. Top. Med. Chem. (2008, 8, 1452-1467);-   Bioorg. Med. Chem. (2010, 18, 5738-5748);-   Eur. J. Pharmacol. (2010, 632, 93-102);-   J. Chem. Inf. Model. (2011, 51, 115-129); and-   Br. J. Pharmacol. (2015, 172, 3805-3816).

Nevertheless, there remains a need to identify and develop new kinaseinhibitors, specifically alternative p38 MAP kinase inhibitors that aresuitable for the treatment of inflammation. There is particularly a needfor such inhibitors that have improved therapeutic potential overcurrently available treatments or, in particular, that exhibit asuperior therapeutic index (e.g. inhibitors that are at least equallyefficacious and, in one or more respects, are less toxic at the relevanttherapeutic dose than previous agents).

SUMMARY OF THE INVENTION

We have now discovered, surprisingly, that certain aniline-substituteddiarylureas inhibit one or more of p38 MAP kinase, Syk and Src familykinases and therefore possess good anti-inflammatory properties.

Thus, according to a first aspect of the invention, there is provided acompound of formula I,

wherein:R^(1A) represents

-   -   C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, which        latter four groups are optionally substituted by one or more        substituents selected from C₁₋₂ alkyl, halo, hydroxy,        —OP(O)(OH)₂ and C₁₋₂ alkoxy,    -   H, halo, cyano,    -   phenyl or Het¹, which latter two groups are optionally        substituted with one or more substituents selected from C₁₋₂        alkyl and C₁₋₂ alkoxy,        or R^(1A) and R^(1B) together represent a structural fragment        selected from the following

wherein the wavy lines represent the points of attachment to the phenylring;A represents O, S or N(R^(A2));R^(A1) represents H, C₁₋₄ alkyl or hydroxy;R^(A2) represents H or C₁₋₄ alkyl;R^(1B) represents —NR^(X)S(O)₂R^(Y1), —C(O)NR^(X)R^(Y), H, halo, cyano,—C₁₋₄ alkylene-CN, —C₁₋₄ alkylene-OH, —NR^(X)R^(X1), —C(O)OR^(X),—S(O)₂NR^(X)R^(Y), —NR^(X)C(O)R^(Y), —NR^(X2)S(O)₂NR^(X)R^(Y),—NR^(X)P(O)R^(Y1)R^(Y2), —NR^(X)C(O)OR^(Y1) or Het¹ optionallysubstituted with one or more substituents selected from halo, hydroxy,C₁₋₂ alkyl and C₁₋₂ alkoxy;R^(X) and R^(X1) independently represent H or C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from halo, hydroxy,—OP(O)(OH)₂ and C₁₋₂ alkoxy, or R^(X) and R^(X1) together represent C₃₋₆n-alkylene or C₄₋₅ n-alkylene interrupted between C2 and C3 by —O— or—N(R^(X2))—, or R^(X1) represents Het¹ optionally substituted with oneor more substituents selected from halo, hydroxy, C₁₋₂ alkyl and C₁₋₂alkoxy;R^(Y), R^(Y1) and R^(Y2) independently represent C₁₋₆ alkyl, C₃₋₇cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six groups areoptionally substituted by one or more substituents selected from C₁₋₂alkyl, halo, hydroxy, —OP(O)(OH)₂, C₁₋₂ alkoxy, C(O)OH, C(O)O—(C₁₋₄alkyl) and —N(R^(a))(R^(b)), and/or which Het² group is substituted withone or more oxo groups,or R^(Y) represents H,or R^(X) and R^(Y) together represent C₃₋₆ n-alkylene or C₄₋₅ n-alkyleneinterrupted between C2 and C3 by —O—, —S(O)_(n)— or —N(R^(X2))—;R^(a) and R^(b) independently represent H, methyl or—C(R^(c))(R^(d))—C₁₋₃ alkyl, the C₁₋₃ alkyl portion of which lattergroup is optionally substituted by one or more hydroxy substituents,or R^(a) and R^(b) together represent C₃₋₆ n-alkylene or C₄₋₅ n-alkyleneinterrupted between C2 and C3 by —O—, —S(O)_(m)— or —N(R^(X2))—;R^(c) and R^(d) independently represent H or methyl;each R^(X2) independently represents H or C₁₋₄ alkyl;R^(1C) and R^(1E) independently represent H, halo, cyano or methyl;provided that at least one of R^(1A), R^(1B), R^(1C) and R^(1E) is otherthan H;R^(1D) represents trimethylsilyl, C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, phenyl, Het¹ or Het², which latter sevengroups are optionally substituted by one or more substituents selectedfrom C₁₋₂ alkyl, halo, cyano, hydroxy, —OP(O)(OH)₂ and C₁₋₂ alkoxy;R² and R³, together with the C-atoms to which they are attached, form afused phenyl or pyridyl ring, which latter two rings are optionallysubstituted by one or more substituents selected from C₁₋₃ alkyl, C₁₋₃haloalkyl, cyano and halo,or one of R² and R³ represents H, halo, cyano, C₁₋₃ alkyl or C₁₋₃haloalkyl and the other independently represents halo, cyano, C₁₋₃ alkylor C₁₋₃ haloalkyl,or R² and R³ together combine to form C₃₋₅ alkylene or C₃₋₅ alkenylene,which latter two groups are optionally substituted by one or moresubstituents selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano and halo;X¹ represents N or CH;L represents a direct bond or C₁₋₂ alkylene;X² represents CR^(Z) or N;X³ represents CR^(5b) or N;R^(Z) represents H, halo, cyano, hydroxy, C₁₋₃ alkyl or C₁₋₃ alkoxy,which latter two groups are optionally substituted by one or more haloatoms;R⁴ represents

-   -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅        alkylene group is optionally substituted by oxo and/or by one or        more R^(6e),    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e) and        which Het^(x1) group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₃₋₆ cycloalkyl,        C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₄ alkyl, the C₁₋₄ alkyl part of        which latter group is optionally substituted by one or more        R^(6e),    -   -Q²²-[C₁₋₄ alkylene]₀₋₁-phenyl, which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e), and        which phenyl group is substituted by —[C(O)]₀₋₁—C₁₋₄ alkyl, the        C₁₋₄ alkyl part of which latter group is optionally substituted        by one or more R^(6e), and which phenyl group is optionally        further substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl and C₁₋₃ alkoxy,    -   —S(O)_(p)R^(6b),    -   —[C₁₋₄ alkylene]₀₋₁-CO₂H,    -   Het^(x2) which Het^(x2) group is optionally substituted by one        or more substituents selected from halo, hydroxy, oxo, C₁₋₃        alkyl and C₁₋₃ alkoxy,    -   —COR^(6b),    -   —CH₂OH,    -   —CH₂OP(O)(OH)₂ or    -   -Q⁴-P(O)(OR⁹)(R⁷);        Z represents, independently upon each occurrence, O, C(O)N(R⁸)        or N(R⁸)C(O);        R^(5a) and R^(5b) independently represent C₁₋₃ alkoxy or C₁₋₃        alkyl, which latter two groups are optionally substituted by one        or more halo atoms, or R^(5a) and R^(5b) independently represent        —N(R^(e))(R^(f)), C₂₋₃ alkynyl, H, cyano, —C(O)NH₂, hydroxy,        halo or —S(O)₀₋₂—C₁₋₃ alkyl;        R^(6a) represents OR^(7a), —S(O)₀₋₂R^(7aa), N(R^(7b))R^(7c) or        CO₂H;        R^(6b) represents C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, Het¹ or        Het², which latter five groups are optionally substituted by one        or more substituents selected from halo, hydroxy, —OP(O)(OH)₂,        C₁₋₃ alkyl, C₁₋₃ alkoxy, —C₁₋₃ alkylene-R^(6e) and CO₂H,        or R^(6b) represents —C₁₋₄ alkylene-Het³, which Het³ group is        optionally substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and        —[C(O)]₀₋₁—C₁₋₃ alkyl, which C₁₋₃ alkyl group is optionally        substituted by one or more R^(6e),        or, when p is 1 or 2, R^(6b) may alternatively represent OH,        or, when p is 2, R^(6b) may alternatively represent        —N(R^(7b))R^(7c) or —N(R^(7b))—C(O)—R^(7c);        R^(6e) represents, independently upon each occurrence, halo,        hydroxy, —OP(O)(OH)₂, C₁₋₃ alkoxy, —N(R^(g))(R^(h)) or —CO₂H;        R^(7a) to R^(7c) independently represent H or C₁₋₄ alkyl        optionally substituted by one or more halo atoms or by —CO₂H,        or R^(7a) represents P(O)(OH)₂ or Het³, which latter group is        optionally substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and        —[C(O)]₀₋₁—C₁₋₃ alkyl, which C₁₋₃ alkyl group is optionally        substituted by one or more R^(6e),        or R^(7b) and/or R^(7c) represents —[C_(a) alkylene]-[C_(b)        alkylene]-OR^(7d),        or R^(7b) and R^(7c) together with the N-atom to which they are        attached, form a 4- to 7-membered heterocyclic group that is        fully saturated, partially unsaturated or fully aromatic and        which heterocyclic group contains one N atom (the atom to which        R^(7b) and R^(7c) are attached) and, optionally, one or more        further heteroatoms selected from O, S and N, and which        heterocyclic group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄        alkoxy and C₁₋₄ hydroxyalkyl;        a and b independently represent an integer selected from 1, 2        and 3, wherein the sum of a and b is 2, 3 or 4;        R^(7d) represents H or C₁₋₄ alkyl optionally substituted by one        or more halo atoms;        R^(7aa) represents —C(R^(7d))(R^(7e))—C₁₋₃ alkylene-OH or C₁₋₄        alkyl optionally substituted by one or more halo atoms or by        —CO₂H;        Q¹, Q², Q²² and Q³ independently represent —C(O)N(R⁸)—, —O— or        —S(O)₂N(R⁸)—, or Q¹, Q² and Q²² independently represent        S(O)_(q);        Q⁴ represents a direct bond or C₁₋₃ alkylene;        n, m, p and q independently represent 0, 1 or 2;        R^(6c), R^(6d), R^(e), R^(f), R^(g), R^(h) and R⁸ independently        represent H or methyl,        or R^(6c) and R^(6d) independently represent hydroxymethyl;        R⁷ represents H, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₇        cycloalkyl or phenyl, which latter four groups are optionally        substituted by one or more substituents selected from halo, OH,        C₁₋₃ alkyl and C₁₋₃ alkoxy;        R⁹ represents H or C₁₋₄ alkyl, which latter group is optionally        substituted by one or more halo atoms or by phenyl, which phenyl        group is optionally substituted by one or more substituents        selected from halo, OH, C₁₋₃ alkyl and C₁₋₃ alkoxy;        Het^(x1) and Het^(x2) independently represent Het^(1a) or Het³;        Het¹ and Het^(1a) represent, independently upon each occurrence,        a 5- or 6-membered heterocyclic group that is fully aromatic,        which group contains one or more heteroatoms selected from N, O        and S; and        Het² and Het³ represent, independently upon each occurrence, a        4- to 9-membered heterocyclic group that is fully saturated or        partially unsaturated, and is monocyclic or is fused or bridged        bicyclic, which group contains one or more heteroatoms selected        from N, O and S;        or a pharmaceutically acceptable salt thereof,        which compounds may be referred to hereinafter as “the compounds        of the invention”.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals.

For the avoidance of doubt, compounds of formula I may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which:

-   (a) the compound of formula I is not isotopically enriched or    labelled with respect to any atoms of the compound; and-   (b) the compound of formula I is isotopically enriched or labelled    with respect to one or more atoms of the compound.

References herein to an “isotopic derivative” relate to the second ofthese two embodiments. In particular embodiments of the invention, thecompound of formula I is isotopically enriched or labelled (with respectto one or more atoms of the compound) with one or more stable isotopes.Thus, the compounds of the invention that may be mentioned include, forexample, compounds of formula I that are isotopically enriched orlabelled with one or more atoms such as deuterium or the like.

Compounds of formula I may exhibit tautomerism. All tautomeric forms andmixtures thereof are included within the scope of the invention.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms, be branched. Particular alkylgroups that may be mentioned include, for example, methyl, ethyl,n-propyl, iso-propyl, butyl, n-butyl and tert-butyl. Particular alkoxygroups that may be mentioned include, for example, methoxy, ethoxy,propoxy, and butoxy.

Unless otherwise specified, cycloalkyl groups as defined herein may,when there is a sufficient number (i.e. a minimum of four) of carbonatoms, be part cyclic/acyclic.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched. In particular embodiments of theinvention, alkylene refers to straight-chain alkylene.

Unless otherwise stated, the point of attachment of aryl groups may bevia any atom of the ring system. However, when aryl groups are bicyclicor tricyclic, they are linked to the rest of the molecule via anaromatic ring. C₆₋₁₄ aryl groups include phenyl, naphthyl and the like.Embodiments of the invention that may be mentioned include those inwhich aryl is phenyl.

For the avoidance of doubt, oxo substituents that may be present onheterocyclic groups represented by Het², Het³ or N(R^(7b))R^(7c) may beattached to any appropriate atoms in the heterocyclic ring including,where valencies allow, to C—, N— and/or S— atoms within the ring(thereby forming keto, N-oxide, S(O) and/or S(O)₂ groups).

Values of Het^(1a) that may be mentioned include imidazolyl (e.g.imidazol-4-yl) and tetrazolyl (e.g. tetrazol-5-yl).

Values of Het² that may be mentioned include piperazinyl (e.g.piperazin-1-yl), piperidinyl (e.g. piperidin-1-yl) and pyrrolidinyl(e.g. pyrrolidin-1-yl).

Values of Het³ that may be mentioned include dihydropyridinyl (e.g.1,2-dihydropyridin-1-yl), homomorpholinyl (e.g. homomorpholin-4-yl),morpholinyl (e.g. morpholin-4-yl), homopiperazinyl (e.g.homopiperazin-1-yl), piperazinyl (e.g. piperazin-1-yl), piperidinyl(e.g. piperidin-1-yl or piperidin-4-yl), pyranyl (e.g. pyran-2-yl orpyran-3-yl), pyridinyl (e.g. pyridin-3-yl or pyridin-4-yl), pyrrolidinyl(e.g. pyrrolidin-1-yl), thiomorpholinyl (e.g. thiomorpholin-4-yl) andquinuclidinyl (e.g. quinuclidin-4-yl).

Unless otherwise specified, the term “halo” includes references tofluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo,especially fluoro or chloro.

Embodiments of the invention that may be mentioned include those inwhich:

-   (a) R^(1A) represents    -   C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, which        latter four groups are optionally substituted by one or more        substituents selected from C₁₋₂ alkyl, halo, hydroxy, and C₁₋₂        alkoxy,    -   H, halo, cyano,    -   phenyl or Het¹, which latter two groups are optionally        substituted with one or more substituents selected from C₁₋₂        alkyl and C₁₋₂ alkoxy,-    or R^(1A) and R^(1B) together represent a structural fragment    selected from the following

-    wherein the wavy lines represent the points of attachment to the    phenyl ring;-   (b) R^(X) and R^(X1) independently represent H or C₁₋₆ alkyl, or    R^(X) and R^(X1) together represent C₃₋₆ n-alkylene or C₄₋₅    n-alkylene interrupted between C2 and C3 by —O— or —N(R^(X2))—, or    R^(X1) represents Het¹ optionally substituted with one or more    substituents selected from halo, hydroxy, C₁₋₂ alkyl and C₁₋₂    alkoxy;-   (c) R^(Y), R^(Y1) and R^(Y2) independently represent C₁₋₆ alkyl,    C₃₋₇ cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six    groups are optionally substituted by one or more substituents    selected from C₁₋₂ alkyl, halo, hydroxy, C₁₋₂ alkoxy, C(O)OH,    C(O)O—(C₁₋₄ alkyl) and —N(R^(a))(R^(b)), and/or which Het² group is    substituted with one or more oxo groups,-    or R^(Y) represents H,-    or R^(X) and R^(Y) together represent C₃₋₆ n-alkylene or C₄₋₅    n-alkylene interrupted between C2 and C3 by —O—, —S(O)_(n)— or    —N(R^(X2))—;-   (d) R^(1D) represents trimethylsilyl, C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇    alkynyl, C₃₋₇ cycloalkyl, phenyl, Het¹ or Het², which latter seven    groups are optionally substituted by one or more substituents    selected from C₁₋₂ alkyl, halo, cyano, hydroxy and C₁₋₂ alkoxy;-   (e) X³ represents CR^(5b);-   (f) R⁴ represents    -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁        CH₂—O]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅        alkylene group is optionally substituted by oxo,    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is optionally        substituted by one or more substituents selected from halo,        hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy and C₁₋₃ hydroxyalkyl,    -   —S(O)_(p)R^(6b),    -   —CO₂H,    -   Het^(1a),    -   —COR^(6b) or    -   —CH₂OH;-   (g) R^(6a) represents OR^(7a), N(R^(7b))R^(7c) or CO₂H;-   (h) R^(6b) represents C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, Het¹ or    Het², which latter five groups are optionally substituted by one or    more substituents selected from halo, hydroxyl, C₁₋₃ alkyl and C₁₋₃    alkoxy;-   (i) R^(7a) to R^(7c) independently represent H or C₁₋₄ alkyl    optionally substituted by one or more halo atoms,-    or R^(7a) represents P(O)(OH)₂,-    or R^(7b) and/or R^(7c) represents —[C_(a) alkylene]-[C_(b)    alkylene]-OR^(7d),-    or R^(7b) and R^(7c) together with the N-atom to which they are    attached, form a 4- to 7-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(7b) and    R^(7c) are attached) and, optionally, one or more further    heteroatoms selected from O, S and N, and which heterocyclic group    is optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy and C₁₋₄ hydroxyalkyl;-   (j) R^(6c) and R^(6d) independently represent H or methyl; and-   (k) R^(5a) and R^(5b) independently represent C₁₋₃ alkoxy or C₁₋₃    alkyl, which latter two groups are optionally substituted by one or    more halo atoms, or R^(5a) and R^(5b) independently represent    —N(R^(e))(R^(f)), C₂₋₃ alkynyl, H, cyano, —C(O)NH₂, hydroxy or halo.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I:

-   (a1) R^(1A) represents C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, which latter four groups are substituted by —OP(O)(OH)₂ and    are optionally further substituted by one or more substituents    selected from C₁₋₂ alkyl, halo, hydroxy, —OP(O)(OH)₂ and C₁₋₂    alkoxy;-   (b1) R^(X) or R^(X1) represents C₁₋₆ alkyl substituted by one or    more substituents selected from halo, hydroxy, —OP(O)(OH)₂ and C₁₋₂    alkoxy;-   (c1) R^(Y), R^(Y1) and R^(Y2) independently represent C₁₋₆ alkyl,    C₃₋₇ cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six    groups are substituted by —OP(O)(OH)₂ and are optionally further    substituted by one or more substituents selected from C₁₋₂ alkyl,    halo, hydroxy, —OP(O)(OH)₂, C₁₋₂ alkoxy, C(O)OH, C(O)O—(C₁₋₄ alkyl)    and —N(R^(a))(R^(b)), and which Het² group is optionally further    substituted with one or more oxo groups;-   (d1) R^(1D) represents C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇    cycloalkyl, phenyl, Het¹ or Het², which latter seven groups are    substituted by —OP(O)(OH)₂ and are optionally further substituted by    one or more substituents selected from C₁₋₂ alkyl, halo, cyano,    hydroxy, —OP(O)(OH)₂ and C₁₋₂ alkoxy;-   (e1) X³ represents N;-   (f1) R⁴ represents    -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)        in which at least one occurrence of Z represents C(O)NH or        NHC(O);    -   -Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅        alkylene group is substituted by R^(6e) and is optionally        further substituted by oxo and/or by one or more R^(6e),    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(1a), which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e) and        which Het^(1a) group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₃₋₆ cycloalkyl,        C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, the C₁₋₃ alkyl part of        which latter group is optionally substituted by one or more        R^(6e);    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het³, which C₁₋₄ alkylene group is        substituted by oxo and/or by one or more R^(6e) and which Het³        group is optionally substituted by one or more substituents        selected from halo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy        and —[C(O)]₀₋₁—C₁₋₃ alkyl, the C₁₋₃ alkyl part of which latter        group is optionally substituted by one or more R^(6e);    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is substituted by        -   C₃₋₆ cycloalkyl,        -   C₁₋₃ alkyl substituted by halo, C₁₋₃ alkoxy,            —N(R^(g))(R^(h)) or —CO₂H and optionally further substituted            by one or more R^(e) or        -   —C(O)—C₁₋₃ alkyl, the C₁₋₃ alkyl part of which latter group            is optionally substituted by one or more R^(6e),    -   and which Het³ group is optionally further substituted by one or        more substituents selected from halo, hydroxy, oxo, C₃₋₆        cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, the C₁₋₃        alkyl part of which latter group is optionally substituted by        one or more R^(6e),    -   Het^(1a) substituted by one or more substituents selected from        halo, hydroxy, oxo, C₁₋₃ alkyl and C₁₋₃ alkoxy,    -   Het³ optionally substituted by one or more substituents selected        from halo, hydroxy, oxo, C₁₋₃ alkyl and C₁₋₃ alkoxy,    -   —CH₂OP(O)(OH)₂ or    -   -Q⁴-P(O)(OR⁹)(R⁷) (e.g. —P(O)(OR⁹)(R⁷));-   (g1) R⁴ represents    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e) and        which Het^(x1) group is substituted by —[C(O)]₀₋₁—C₄ alkyl, the        C₄ alkyl part of which latter group is optionally substituted by        one or more R^(6e), and which Het^(x1) group is optionally        further substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and        —[C(O)]₀₋₁—C₁₋₄ alkyl, the C₁₋₄ alkyl part of which latter group        is optionally substituted by one or more R^(6e),    -   -Q²²-[C₁₋₄ alkylene]₀₋₁-phenyl, which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e), and        which phenyl group is substituted by —[C(O)]₀₋₁—C₁₋₄ alkyl, the        C₁₋₄ alkyl part of which latter group is optionally substituted        by one or more R^(6e), and which phenyl group is optionally        further substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl and C₁₋₃ alkoxy, —C₁₋₄        alkylene-CO₂H,-   (h1) R^(6a) represents —S(O)₀₋₂R^(7aa);-   (i1) R^(6b) represents    -   C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, Het¹ or Het², which latter        five groups are substituted by —OP(O)(OH)₂, —C₁₋₃        alkylene-R^(6e) or CO₂H and are optionally further substituted        by one or more substituents selected from halo, hydroxy,        —OP(O)(OH)₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, —C₁₋₃ alkylene-R^(6e) and        CO₂H or    -   —C₁₋₄ alkylene-Het³, which Het³ group is optionally substituted        by one or more substituents selected from halo, hydroxy, oxo,        C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, which        C₁₋₃ alkyl group is optionally substituted by one or more        R^(6e),    -   or, when p is 1 or 2, R^(6b) may alternatively represent OH    -   or, when p is 2, R^(6b) may alternatively represent        —N(R^(7b))R^(7c) or —N(R^(7b))—C(O)—R^(7c),-   (j1) R^(7a) represents Het³, which latter group is optionally    substituted by one or more substituents selected from halo, hydroxy,    oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, which    C₁₋₃ alkyl group is optionally substituted by one or more R^(6e),-   (k1) R^(7a), R^(7aa), R^(7b) and/or R^(7c) represents C₁₋₄ alkyl    substituted by —CO₂H;-   (l1) R^(6c) and/or R^(6d) represents hydroxymethyl;-   (m1) R^(5a) and/or R^(5b) represents —S(O)₀₋₂—C₁₋₃ alkyl.

In particular, embodiments of the invention that may be mentionedinclude those in which any one or more of (e1), (g1), (k1) and (m1)above apply.

Other embodiments of the invention that may be mentioned include thosein which:

-   (1) X³ represents CR^(5b);-   (2) R⁴ represents    -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁        CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅        alkylene group is optionally substituted by oxo and/or by one or        more R^(6e),    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e) and        which Het^(x1) group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₃₋₆ cycloalkyl,        C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, the C₁₋₃ alkyl part of        which latter group is optionally substituted by one or more        R^(6e),    -   —S(O)_(p)R^(6b),    -   —CO₂H,    -   Het^(x2) which Het^(x2) group is optionally substituted by one        or more substituents selected from halo, hydroxy, oxo, C₁₋₃        alkyl and C₁₋₃ alkoxy,    -   —COR^(6b),    -   —CH₂OH,    -   —CH₂OP(O)(OH)₂ or    -   -Q⁴-P(O)(OR⁹)(R⁷);-   (3) R^(7a) to R^(7c) independently represent H or C₁₋₄ alkyl    optionally substituted by one or more halo atoms,-    or R^(7a) represents P(O)(OH)₂ or Het³, which latter group is    optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and-    -[C(O)]₀₋₁—C₁₋₃ alkyl, which C₁₋₃ alkyl group is optionally    substituted by one or more R^(6e),-    or R^(7b) and/or R^(7c) represents —[C_(a) alkylene]-[C_(b)    alkylene]-OR^(7d),-    or R^(7b) and R^(7c) together with the N-atom to which they are    attached, form a 4- to 7-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(7b) and    R^(7c) are attached) and, optionally, one or more further    heteroatoms selected from O, S and N, and which heterocyclic group    is optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy and C₁₋₄ hydroxyalkyl;-   (4) R^(7aa) represents —C(R^(7d))(R^(7e))—C₁₋₃ alkylene-OH or C₁₋₄    alkyl optionally substituted by one or more halo atoms; and-   (5) R^(5a) and R^(5b) independently represent C₁₋₃ alkoxy or C₁₋₃    alkyl, which latter two groups are optionally substituted by one or    more halo atoms, or R^(5a) and R^(5b) independently represent    —N(R^(e))(R^(f)), C₂₋₃ alkynyl, H, cyano, —C(O)NH₂, hydroxy or halo.

In particular, such other embodiments of the invention that may bementioned include those in which (1) to (5) above all apply and any oneor more of (a1) to (d1), (f1), (h1) to (j1) and (l1) apply.

Particular embodiments of the invention that may be mentioned includethose in which, in the compound of formula I, R⁴ represents

-   -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁        CH₂—R^(6a),    -   -Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅        alkylene group is optionally substituted by oxo and/or by one or        more R^(6e),    -   -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e) and        which Het^(x1) group is optionally substituted by one or more        substituents selected from halo, hydroxy, oxo, C₃₋₆ cycloalkyl,        C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₄ alkyl (e.g. —[C(O)]₀₋₁—C₁₋₃        alkyl), the C₁₋₄ alkyl part of which latter group is optionally        substituted by one or more R^(6e),    -   -Q²²-[C₁₋₄alkylene]₀₋₁-phenyl, which C₁₋₄ alkylene group is        optionally substituted by oxo and/or by one or more R^(6e), and        which phenyl group is substituted by —[C(O)]₀₋₁—C₁₋₄ alkyl, the        C₁₋₄ alkyl part of which latter group is optionally substituted        by one or more R^(6e), and which phenyl group is optionally        further substituted by one or more substituents selected from        halo, hydroxy, oxo, C₃₋₆ cycloalkyl and C₁₋₃ alkoxy,    -   —S(O)_(p)R^(6b),    -   —C₁₋₄ alkylene-CO₂H (e.g. —CO₂H),    -   Het^(x2) which Het^(x2) group is optionally substituted by one        or more substituents selected from halo, hydroxy, oxo, C₁₋₃        alkyl and C₁₋₃ alkoxy,    -   —COR^(6b),    -   —CH₂OH,    -   —CH₂OP(O)(OH)₂ or    -   —P(O)(OR⁹)(R⁷).

Other embodiments of the invention that may be mentioned include thosein which, in the compound of formula I, R⁴ represents —C₁₋₃alkylene-P(O)(OR⁹)(R⁷).

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I:

-   (a) R^(1A) represents C₁₋₄ alkoxy, C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄    alkynyl, which latter four groups are optionally substituted by one    or more halo substituents, or R^(1A) represents H, halo or cyano;-   (b) R^(1B) represents —NR^(X)S(O)₂R^(Y1), —C(O)NR^(X)R^(Y), H, halo,    cyano, —C₁₋₂ alkylene-CN, —C₁₋₂ alkylene-OH, —S(O)₂NR^(X)R^(Y),    —NR^(X)C(O)R^(Y), —NR^(X2)S(O)₂NR^(X)R^(Y) or Het¹, which latter    group is optionally substituted with one or more substituents    selected from halo, hydroxy, methyl and methoxy;-   (c) R^(X) represents H or C₁₋₃ alkyl optionally substituted by    hydroxy or —OP(O)(OH)₂ (e.g. R^(X) represents H or C₁₋₃ alkyl);-   (d) R^(Y) and R^(Y1) independently represent C₁₋₄ alkyl, C₄₋₆    cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six groups    are optionally substituted by one or more substituents selected from    methyl, halo, hydroxy, —OP(O)(OH)₂, methoxy, NH₂, N(H)CH₃, N(CH₃)₂,    C(O)OH and C(O)OCH₃ (e.g. by one or more substituents selected from    methyl, halo, hydroxy, methoxy, NH₂, N(H)CH₃, N(CH₃)₂, C(O)OH and    C(O)OCH₃),-    or R^(Y) represents H,-    or R^(X) and R^(Y) together represent C₄₋₅ n-alkylene optionally    interrupted between C2 and C3 by —O— or —N(R^(X2))—;-   (e) each R^(X2) independently represents H or methyl;-   (f) R^(1C) and R^(1E) independently represent H or halo;-   (g) R^(1D) represents trimethylsilyl, C₂₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅    alkynyl, C₃₋₆ cycloalkyl, phenyl, Het¹ or Het², which latter seven    groups are optionally substituted by one or more substituents    selected from methyl, halo, cyano, hydroxy and methoxy;-   (h) R² and R³, together with the C-atoms to which they are attached,    form a fused phenyl ring, which ring is optionally substituted by    one or more halo groups,-    or one of R² and R³ represents H, halo, cyano, methyl or halomethyl    and the other independently represents halo, cyano, methyl or    halomethyl,-    or R² and R³ together combine to form C₃₋₄ alkylene or C₃₋₄    alkenylene, which latter two groups are optionally substituted by    one or more substituents selected from methyl, halomethyl, cyano and    halo;-   (i) X¹ represents N or CH;-   (j) L represents CH₂ or, particularly, a direct bond;-   (k) X² represents N or, particularly, CR^(Z);-   (l) R^(Z) represents halo, cyano, methyl or methoxy, which latter    two groups are optionally substituted by one or more halo atoms, or,    particularly, R^(Z) represents H;-   (m) X³ represents CR^(5b);-   (n) R⁴ represents-    -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁—CH₂—Z]₁₋₆—CH₂CH₂—R^(6a)-    -Q²-C(R^(6c))(R^(6d))—[C₁₋₄ alkylene]-R^(6a), which C₁₋₄ alkylene    group is optionally substituted by oxo and/or by one or more R^(6e)    (e.g. by one or more substituents selected from halo, hydroxy and    —N(R^(g))(R^(h))),-    -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is    optionally substituted by oxo and/or by one or more R^(6e) (e.g. by    one or more substituents selected from halo, hydroxy,    —N(R^(g))(R^(h)) and —CO₂H) and which Het^(x1) group is optionally    substituted by one or more substituents selected from halo, hydroxy,    oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ hydroxyalkyl, C₃₋₅ cycloalkyl and    —C(O)—C₁₋₃ alkyl, the C₁₋₃ alkyl part of which latter group is    optionally substituted by one or more R^(6e) (e.g. by one or more    substituents selected from halo, hydroxy, —N(R^(g))(R^(h)) and    —CO₂H)-    —S(O)₀₋₂R^(6b),-    CO₂H,-    Het^(1a) optionally substituted by one or more substituents    selected from halo, hydroxy, methyl and methoxy,-    Het³ optionally substituted by one or more substituents selected    from oxo, hydroxy and methyl,-    —COR^(6b) or-    -Q⁴-P(O)(OR⁹)(R⁷) (e.g. —P(O)(OR⁹)(R⁷))-    (e.g. R⁴ represents-    -Q¹-[C(R^(6c))(R^(6d))—CH₂—O]₁₋₆CH₂CH₂—R^(6a),-    -Q²-C(R^(6c))(R^(6d))—[C₁₋₄ alkylene]-R^(6a), which C₁₋₄ alkylene    group is optionally substituted by oxo,-    -Q³-[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is optionally    substituted by one or more substituents selected from halo, hydroxy,    oxo, methyl, methoxy and C₁₋₂ hydroxyalkyl, —S(O)₀₋₂R^(6b),-    Het^(1a), or-    CO₂H);-   (o) R^(5a) and R^(5b) independently represent C₁₋₂ alkoxy or C₁₋₂    alkyl, which latter two groups are optionally substituted by one or    more halo atoms, or R^(5a) and R^(5b) independently represent    —N(CH₃)₂, C₂₋₃ alkynyl, H, cyano or halo;-   (p) R^(6a) represents CO₂H or, particularly, OR^(7a) or    N(R^(7b))R^(7c);-   (q) R^(6b) represents    -   Het² optionally substituted by one or more substituents selected        from halo, hydroxy, methyl, methoxy, CO₂H and —C₁₋₃        alkylene-R^(6e) (wherein R^(6e) is as hereinbefore defined or,        particularly, represents hydroxy or —N(R^(g))(R^(h)))    -   C₁₋₄ alkyl or C₄₋₆ cycloalkyl, which latter two groups are        optionally substituted by one or more substituents selected from        halo, methyl and methoxy    -   or, when p is 1 or 2, R^(6b) may alternatively represent OH    -   or, when p is 2, R^(6b) may alternatively represent —N(H)R^(7c)        or —N(H)—C(O)—R^(7c)(e.g. R^(6b) represents C₁₋₄ alkyl or C₄₋₆        cycloalkyl, which latter two groups are optionally substituted        by one or more substituents selected from halo, methyl and        methoxy);-   (r) R⁷ represents H, hydroxy, C₁₋₃ alkyl or phenyl;-   (s) R⁹ represents H or C₁₋₃ alkyl (e.g. ethyl);-   (t) R^(7a) represents    -   Het³ optionally substituted by one or more substituents selected        from halo, hydroxy, oxo, C₁₋₃ alkyl and C₁₋₃ hydroxyalkyl or,        particularly,    -   H    -   C₁₋₃ alkyl optionally substituted by one or more halo atoms, or    -   P(O)(OH)₂;-   (u) R^(7b) and R^(7c) independently represent H or C₁₋₃ alkyl (e.g.    ethyl or, particularly, methyl) optionally substituted by one or    more halo atoms,-    or R^(7b) represents H or methyl and R^(7c) represents —[C₁₋₃    alkylene]-CH₂—OR^(7d),-    or R^(7b) and R^(7c), together with the N-atom to which they are    attached, form a 5- to 7-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(7b) and    R^(7c) are attached) and, optionally, one or more further    heteroatoms selected from O, S and N, and which heterocyclic group    is optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, methyl, methoxy and C₁₋₃ hydroxyalkyl;-   (v) R^(7d) represents H or C₁₋₂ alkyl optionally substituted by one    or more fluoro atoms;-   (w) Q¹, Q² and Q³ independently represent C(O)NR⁸, S(O)₁₋₂, S(O)₂NR⁸    or O (e.g. Q¹, Q² and Q³ independently represent O, C(O)NR⁸ or    S(O)₂NR⁸ or Q¹ and Q² independently represent S(O)₂ or S(O));-   (x) Q⁴ represents CH₂ or, particularly, a direct bond;-   (z) R^(6c), R^(6d) and R⁸ independently represent H or methyl, or    R^(6c) and R^(6d) independently represent hydroxymethyl;-   (z) Het¹ and Het^(1a) represent, independently upon each occurrence,    a 5- or 6-membered heterocyclic group that is fully aromatic, which    group contains one or more heteroatoms selected from N, O and S;-   (aa) Het² and Het³ represent, independently upon each occurrence, a    5- to 8-membered (e.g. a 5- or 6-membered) heterocyclic group that    is fully saturated or partially unsaturated, which group is    monocyclic or is fused or bridged bicyclic and which group contains    one or more heteroatoms selected from N, O and S.

Other embodiments of the invention that may be mentioned include thosein which when R⁴ represents —C(O)N(R⁸)—C(R^(6c))(R^(6d))—[C₁₋₅alkylene]-N(R^(7b))R^(7c), which C₁₋₅ alkylene group is optionallysubstituted by oxo and/or by one or more R^(6e), then:

R^(7b) and R^(7c) both represent H or, particularly,R^(7b) and/or R^(7c) represents —[C_(a) alkylene]-[C_(b)alkylene]-OR^(7d),or R^(7b) and R^(7c) together with the N-atom to which they areattached, form a 4- to 7-membered heterocyclic group that is fullysaturated, partially unsaturated or fully aromatic and whichheterocyclic group contains one N atom (the atom to which R^(7b) andR^(7c) are attached) and, optionally, one or more further heteroatomsselected from O, S and N, and which heterocyclic group is optionallysubstituted by one or more substituents selected from halo, hydroxy,oxo, C₁₋₄ alkyl, C₁₋₄ alkoxy and C₁₋₄ hydroxyalkylor, when R^(1B) represents —C(O)NR^(X)R^(Y), H, halo, cyano, —C₁₋₄alkylene-CN, —C₁₋₄ alkylene-OH, —NR^(X)R^(X1), —C(O)OR^(X),—S(O)₂NR^(X)R^(Y), —NR^(X)C(O)R^(Y), —NR^(X)P(O)R^(Y1)R^(Y2), or Het¹optionally substituted with one or more substituents selected from halo,hydroxy, C₁₋₂ alkyl and C₁₋₂ alkoxy, R^(7b) and/or R^(7c) mayalternatively represent H or C₁₋₄ alkyl optionally substituted by one ormore halo atoms(e.g. when R⁴ represents —C(O)N(R⁸)—C(R^(6c))(R^(6d))—[C₁₋₅alkylene]-N(R^(7b))R^(7c), which C₁₋₅ alkylene group is optionallysubstituted by oxo and/or by one or more R^(6e), then R^(7b) and/orR^(7c) represents —[C_(a) alkylene]-[C_(b) alkylene]-OR^(7d), or R^(7b)and R^(7c) together with the N-atom to which they are attached, form a4- to 7-membered heterocyclic group that is fully saturated, partiallyunsaturated or fully aromatic and which heterocyclic group contains oneN atom (the atom to which R^(7b) and R^(7c) are attached) and,optionally, one or more further heteroatoms selected from O, S and N,and which heterocyclic group is optionally substituted by one or moresubstituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxyand C₁₋₄ hydroxyalkyl).

Embodiments of the invention that may be mentioned include those inwhich the compound of formula I is a compound of formula Ia,

wherein R^(1A) to R^(1E), R² to R⁴, R^(5a), R^(5b), L, X¹ and X² are ashereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I and Ia:

-   (a) R^(1A) represents C₁₋₂ alkoxy (e.g. methoxy) optionally    substituted by one or more halo substituents, or R^(1A) represents    H;-   (b) R^(1B) represents —N(R^(XX))S(O)₂R^(Y1), —C(O)N(R^(XX))R^(Y),    —N(H)C(O)R^(YY) or, particularly, —N(H)S(O)₂R^(Y1), —C(O)N(H)R^(Y),    —S(O)₂N(H)R^(Y), —N(H)C(O)R^(Y) or —N(H)S(O)₂NR^(X)R^(Y);-   (c) R^(XX) represents —CH₂CH₂—OP(O)(OH)₂ or, particularly,    —CH₂CH₂—OH;-   (d) R^(X) represents H or methyl;-   (e) R^(Y) and R^(Y1) independently represent C₁₋₂ alkyl (e.g.    methyl),-    or R^(Y) represents H,-   or R^(X) and R^(Y) together represent C₄₋₅ n-alkylene optionally    interrupted between C2 and C3 by —O— or —N(R^(X2))—;-   (f) R^(YY) represents C₁₋₃ alkyl substituted by hydroxy or    —OP(O)(OH)₂ (e.g. methyl substituted by hydroxy or, particularly,    —OP(O)(OH)₂);-   (g) R^(X2) represents H or methyl;-   (h) R^(1C) and R^(1E) both represent H;-   (i) R^(1D) represents trimethylsilyl, C₃₋₅ alkyl (e.g. C₄ alkyl,    such as tert-butyl), C₃₋₅ alkynyl or Het², which latter three groups    are optionally substituted by cyano, hydroxy or methoxy, and/or    which Het² group is optionally substituted by one or more    substituents selected from methyl and halo;-   (j) R² and R³, together with the C-atoms to which they are attached,    form a fused phenyl ring, or R² and R³ both represent chloro;-   (k) X¹ represents N or, particularly, CH;-   (l) L represents a direct bond;-   (m) X² represents CR^(Z);-   (n) R^(Z) represents H;-   (o) R⁴ represents-    -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁—CH₂—Z]₁₋₃—CH₂CH₂—R^(6a),-    -Q²-C(R^(6c))(R^(6d))—[C₁₋₄ alkylene]-R^(6a), which C₁₋₄ alkylene    group is optionally substituted by oxo and/or by one or more    substituents selected from hydroxy and —N(R^(g))(R^(h)),-    -Q³-[C₁₋₄ alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is    optionally substituted by oxo and/or by one or more substituents    selected from hydroxy, —N(R^(g))(R^(h)) and —CO₂H, and which    Het^(x1) group is optionally substituted by one or more substituents    selected from halo, hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃    hydroxyalkyl, C₃₋₅ cycloalkyl and —C(O)—C₁₋₃ alkyl, the C₁₋₃ alkyl    part of which latter group is optionally substituted by one or more    substituents selected from hydroxy, —N(R^(g))(R^(h)) and —CO₂H-    —S(O)₁₋₂R^(6b),-    Het^(1a) optionally substituted by methyl or hydroxy,-    Het³ optionally substituted by oxo,-    CO₂H,-    —COR^(6b) or-    —P(O)(OR⁹)(R⁷);-    (e.g. R⁴ represents-    -Q¹[C(R^(6c))(R^(6d))—CH₂—O]₁₋₃—CH₂CH₂—R^(6a),-    -Q²-C(R^(6c))(R^(6d))—[C₁₋₃ alkylene]-R^(6a), which C₁₋₃ alkylene    group is optionally substituted by oxo,-    —C(O)NR⁸—[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is optionally    substituted by one or more substituents selected from hydroxy, oxo,    methyl, methoxy and C₁₋₂ hydroxyalkyl, —S(O)₁₋₂R^(6b),-    tetrazolyl, or-    CO₂H);-   (p) R^(5a) and R^(5b) independently represent H or C₁₋₂ alkoxy (e.g.    methoxy), or R^(5a) represents OH, halo, C₁₋₂ alkyl or,    particularly, —N(CH₃)₂, ethynyl or cyano;-   (q) Z represents, independently upon each occurrence, C(O)NH, NHC(O)    or, particularly, O (e.g. all occurrences of Z represent C(O)NH,    NHC(O) or, particularly, O);-   (r) R^(6a) represents CO₂H or, particularly, OR^(7a) or    N(R^(7b))R^(7c);-   (s) R^(6b) represents    -   Het² optionally substituted by one or more substituents selected        from hydroxy, CO₂H, hydroxymethyl and —CH₂CH₂—N(R^(g))(R^(h)),    -   C₁₋₃ alkyl (e.g. methyl)    -   or, when p is 1, R^(6b) may alternatively represent OH    -   or, when p is 2, R^(6b) may alternatively represent —NH₂ or        —N(H)—C(O)—C₁₋₂ alkyl (e.g. R^(6b) represents C₁₋₃ alkyl (e.g.        methyl);-   (t) R^(6c) and R^(6d) independently represent H, methyl or    hydroxymethyl (e.g. R^(6c) represents H, methyl or hydroxymethyl and    R^(6d) represents H, or R^(6c) and R^(6d) both represent    hydroxymethyl)-    or, particularly, R^(6c) and R^(6d) independently represent methyl    or, particularly, H (e.g. R^(6c) and R^(6d) both represent H or    R^(6c) represents methyl and R^(6d) represents H);-   (u) R⁷ represents H, hydroxy, ethyl, phenyl or, particularly,    methyl;-   (v) R⁹ represents H or ethyl;-   (w) R^(7a) represents    -   Het³ optionally substituted by one or more substituents selected        from hydroxy, methyl and hydroxymethyl or, particularly,    -   H, methyl, or P(O)(OH)₂;-   (x) R^(7b) and R^(7c) independently represent H or methyl,-    or R^(7b) represents H or methyl and R^(7x) represents —[C₁₋₂    alkylene]-CH₂—OR^(7d),-    or R^(7b) and R^(7c), together with the N-atom to which they are    attached, form a 5- to 7-membered heterocyclic group that is fully    saturated or partially unsaturated and which heterocyclic group    contains one N atom (the atom to which R^(7b) and R^(7c) are    attached) and, optionally, one further heteroatom selected from O, S    and N, and which heterocyclic group is optionally substituted by one    or more substituents selected from fluoro, hydroxy, oxo, methyl and    C₁₋₂ hydroxyalkyl;-   (y) R^(7d) represents H or C₁₋₂ alkyl;-   (z) Q¹, Q² and Q³ independently represent C(O)NR⁸, S(O)₂, S(O),    S(O)₂NR⁸ or O;-   (aa) R⁸ represents H or methyl;-   (ab) R^(g) and R^(h) independently represent H or methyl (e.g. R^(g)    and R^(h) both represent either H or methyl);-   (ac) Het^(1a) represents a 5- or 6-membered heterocyclic group that    is fully aromatic, which group contains an N-atom and optionally    contains one to three further heteroatoms selected from N, O and S    (e.g. Het^(1a) represents imidazolyl or tetrazolyl);-   (ad) Het² and Het³ represent, independently upon each occurrence, a    5- to 8-membered (e.g. a 5- or 6-membered monocyclic group, or an    8-membered bridged bicyclic group) heterocyclic group that is fully    saturated or partially unsaturated, which group is monocyclic or is    bridged bicyclic and which group contains one or two heteroatoms    selected from N, O and S.

Further embodiments of the invention that may be mentioned include thosein which the compound of formula I or Ia is a compound of formula Ib,

or a pharmaceutically acceptable salt thereof, wherein R^(1A), R^(1B),R^(1D), R⁴, R^(5a), R^(5b), X¹ and X² are as hereinbefore defined.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compounds offormula I, Ia and Ib:

-   (a) R^(1A) represents H or, particularly, methoxy;-   (b) R^(1B) represents —N(CH₂CH₂OH)S(O)₂CH₃,    —N[CH₂CH₂OP(O)(OH)₂]S(O)₂CH₃—C(O)N(H)—CH₂CH₂—OH, —N(H)C(O)CH₂OH,    —N(H)C(O)CH₂OP(O)(OH)₂ or, particularly, —N(H)S(O)₂CH₃ or —C(O)NH₂;-   (c) R^(1D) represents C₄ alkyl, such as tert-butyl;-   (d) X¹ represents N or, particularly, CH;-   (e) X² represents CR^(Z);-   (f) R^(Z) represents H;-   (g) R⁴ represents-    -Q¹-[C(H)(R^(6c))—CH₂—Z]₁₋₃—CH₂CH₂—R^(6a),-    —C(O)NH—[CH₂CH₂CH₂—O]—[CH₂(CH₂)₀₋₁CH₂—O]₀₋₁—CH₂CH₂—R^(6a),-    -Q²-C(R^(6c))(R^(6d))—[C₁₋₄ alkylene]-R^(6a), which C₁₋₃ alkylene    group is optionally substituted by oxo and/or by one or more hydroxy    groups,-    Q³-[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is optionally    substituted by one or more substituents selected from halo, hydroxy,    oxo, C₁₋₃ alkyl (e.g. methyl, ethyl or isopropyl), methoxy, C₃₋₄    cycloalkyl (e.g. cyclopropyl), C₁₋₂ hydroxyalkyl and —C(O)—C₁₋₃    alkyl, the C₁₋₃ alkyl part of which latter group is substituted by    hydroxy, —N(R^(g))(R^(h)) or —CO₂H,-    —C(O)NH—C₁₋₄ alkylene-Het^(1a), which C₁₋₄ alkylene group is    optionally substituted by CO₂H,-    —S(O)₁₋₂CH₃,-    —S(O)OH,-    —S(O)₂NH₂,-    —S(O)₂NH—C(O)—C₁₋₂ alkyl,-    Het^(1a),-    Het³ optionally substituted by oxo,-    CO₂H,-    —C(O)—Het³, which Het³ group is optionally substituted by one or    more substituents selected from hydroxy, CO₂H, hydroxymethyl and    —CH₂CH₂—N(R^(g))(R^(h)),-    —P(O)(O—CH₂CH₃)(R⁷) or-    —P(O)(OH)(R⁷);-    (e.g. R⁴ represents-    -Q¹-[C(H)(R^(6c))—CH₂—O]₁₋₃—CH₂CH₂—R^(6a) (e.g.    -Q¹-[C(H)(R^(6c))—CH₂—O]₁₋₂—CH₂CH₂—R^(6a)),-    -Q²-C(H)(R^(6c))—[C₁₋₃ alkylene]-R^(6a), which C₁₋₃ alkylene group    is optionally substituted by oxo,-    —C(O)NH—[C₁₋₄ alkylene]₀₋₁-Het³, which Het³ group is optionally    substituted by one or more substituents selected from oxo, methyl    and methoxy,-    —S(O)₁₋₂CH₃, or-    CO₂H);-   (h) R^(5a) and R^(5b) independently represent H, methyl, methoxy,    hydroxy, ethynyl, cyano, halo or —N(CH₃)₂-    or, particularly, R^(5a) and R^(5b) independently represent H or    methoxy, or R^(5a) represents ethynyl or cyano (e.g. R^(5a) and    R^(5b) both represent H, both represent methoxy or, particularly,    R^(5a) represents cyano or methoxy and R^(5b) represents H);-   (i) R^(6a) represents CO₂H or, particularly, OR^(7a) or    N(R^(7b))R^(7c);-   (j) R^(6c) represents H, methyl or hydroxymethyl and R^(6d)    represents H, or R^(6c) and R^(6d) both represent hydroxymethyl    (e.g. R^(6d) represents H and R^(6c) represents methyl or,    particularly, H);-   (k) R^(7a) represents    -   Het³ optionally substituted by one or more substituents selected        from hydroxy and hydroxymethyl or, particularly,    -   H, methyl, or P(O)(OH)₂-    (e.g. R^(7a) represents H or, particularly, methyl);-   (l) R^(7b) and R^(7c) independently represent H or methyl,-    or R^(7b) represents H or methyl and R^(7x) represents    —CH₂CH₂—OR^(7d),-    or, particularly, R^(7b) and R^(7c), together with the N-atom to    which they are attached, form-    a 5- to 7-membered heterocyclic group that is fully saturated and    which heterocyclic group contains one N atom (the atom to which    R^(7b) and R^(7c) are attached) and, optionally, one further    heteroatom selected from O, S and N, and which heterocyclic group is    optionally substituted by one or more substituents selected from    hydroxy, oxo, methyl and C₁₋₂ hydroxyalkyl;-   (m) R^(7d) represents H or methyl;-   (n) R⁷ represents ethyl or, particularly, methyl;-   (o) Q¹, Q² and Q³ independently represent S(O)₂, S(O), S(O)₂NR⁸, O,    C(O)N(CH₃) or, particularly, C(O)NH;-   (p) R⁸ represents H or, particularly, methyl;-   (q) Het³ represents a 5- to 7-membered (e.g. a 5- or, particularly,    a 6-membered) heterocyclic group that is fully saturated, which    group contains one or two heteroatoms selected from N, O and S.

Certain embodiments of the invention relate to compounds of formula I,Ia or Ib in which R^(5b) is H and R^(5a) is other than H (e.g. methyl,methoxy, hydroxy, ethynyl, cyano, halo, or —N(CH₃)₂).

Certain other embodiments of the invention relate to compounds offormula I, Ia or Ib in which R^(5a) and R^(5b) are both other than H(e.g. R^(5a) and R^(5b) are independently selected from methyl, methoxy,hydroxy, ethynyl, cyano, halo and —N(CH₃)₂ or, particularly, R^(5a) andR^(5b) are both methoxy).

Particular embodiments of the invention that may be mentioned includethose in which one or more of the following definitions apply to thecompounds of formula I, Ia and Ib:

-   (a) R^(1A) represents methoxy;-   (b) R^(1B) represents —N(H)S(O)₂CH₃;-   (c) R^(1D) represents tert-butyl;-   (d) X¹ represents CH;-   (e) X² represents CH;-   (f) R⁴ represents    -   —C(O)NH—[CH₂CH₂—O]₁₋₂—CH₂CH₂—OR^(7a) or    -   —P(O)(OH)(R⁷);-   (g) R^(7a) represents H or P(O)(OH)₂;-   (h) R⁷ represents methyl;-   (i) R^(5a) represents methoxy;-   (j) R^(5b) represents H or methoxy.

Particular embodiments of the invention that may be mentioned includethose in which, in the compounds of formula I, Ia and Ib, R⁴ represents—P(O)(OR⁹)(R⁷) and R^(1A) to R^(1E), R², R³, X¹, L, X², R^(5a), R^(5b),R⁷ and R⁹ are as defined above (e.g. R^(1A) to R^(1E), R², R³, X¹, L,X², R^(5a) and R^(5b) are as defined in any of the embodiments above andR⁷ represents C₁₋₄ alkyl, such as methyl, and/or R⁹ represents C₁₋₄alkyl (such as ethyl) or, particularly, H).

Other compounds of formula I, Ia or Ib that may be mentioned include thecompounds of the examples described hereinafter. Thus, embodiments ofthe invention that may be mentioned include those in which the compoundof formula I, Ia or Ib is a compound selected from the list:

-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-morpholinoethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-morpholinoethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-cyano-4-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-cyano-4-(2-morpholinoethoxy)anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-cyano-4-(3-morpholinopropoxy)anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[2-[2-(2-methoxyethoxy)ethoxy]ethylsulfinyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[2-[2-(2-methoxyethoxy)ethoxy]ethylsulfonyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[methyl(3-morpholinopropyl)sulfamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1-methyl-4-piperidyl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethynyl-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(3-morpholinopropyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-morpholino-2-oxo-ethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-2-[2-(2-methoxyethoxy)ethoxy]-1-methyl-ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-2-[2-(2-methoxyethoxy)ethoxy]-1-methyl-ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]pyrimidin-2-yl]amino]-2-methoxy-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(1-methyl-4-piperidyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-thiomorpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-hydroxy-1-piperidyl)ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-methyl-2-morpholino-propyl)benzamide;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[methyl(2-morpholinoethyl)sulfamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1-piperidyl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-pyrrolidin-1-ylethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2-methoxy-benzamide;-   5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-1-methyl-2-morpholino-ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-piperazin-1-ylethyl)benzamide;-   3-[2-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethoxy]ethoxy]propanoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(4-morpholinobutyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(4-methylpiperazin-1-yl)propyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-methyl-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-hydroxyethyl(methyl)amino]ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-[2-methoxyethyl(methyl)amino]ethyl]-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-methyl-N-(3-morpholinopropyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(1-oxo-1,4-thiazinan-4-yl)propyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[3-(1,1-dioxo-1,4-thiazinan-4-yl)propyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1,4-oxazepan-4-yl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(1,4-oxazepan-4-yl)propyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1-methyl-4-piperidyl)methyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4,4-difluoro-1-piperidyl)ethyl]-2-methoxy-benzamide;-   2-[2-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxybenzoyl]amino]ethoxy]ethoxy]ethyl    dihydrogen phosphate;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)benzoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(3-morpholinopropyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)acetic    acid;-   4-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)butanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide;-   (S)-2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-(1H-imidazol-4-yl)propanoic    acid;-   (S)-1-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoyl)pyrrolidine-2-carboxylic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxybenzoic    acid;-   3-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(1-methylpiperidin-4-yl)ethyl)    benzenesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)benzene    sulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-(dimethylamino)benzoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(5-(dimethylamino)pentyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-ethylpiperazin-1-yl)ethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-isopropylpiperazin-1-yl)ethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)-2-methoxy    benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2,2,4-trimethylpiperazin-1-yl)ethyl)benzamide;-   (S)-2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-hydroxypropanoic    acid;-   N-((4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)sulfonyl)propionamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(1-(4-methylpiperazin-1-yl)propan-2-yl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-hydroxyethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzamide;-   4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)    benzamide;-   (S)-2-amino-6-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-(((3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)    benzamide;-   6-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-((1-methylpiperidin-4-yl)methyl)benzamide;-   3-(3-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propoxy)propanoic    acid;-   2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethyl    dihydrogen phosphate;-   4-((2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)amino)-4-oxobutanoic    acid;-   3-(3-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propanamido)propanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(3-oxo-3-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)propyl)benzamide;-   N-(5-(tert-butyl)-3-(3-(4-((2-((4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)-3,5-dimethoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methane    sulfonamide;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((3-(4-methylpiperazin-1-yl)propyl)    sulfonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidine-1-carbonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)ethyl)-2-methoxybenzamide;-   4-(4-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)piperazin-1-yl)-4-oxobutanoic    acid;-   (S)-2-amino-5-(4-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)piperazin-1-yl)-5-oxopentanoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,2-bis(hydroxymethyl)propyl)-2,6-dimethoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)methyl)benzamide;-   2-((5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)-ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)amino)-2-oxoethyl    dihydrogen phosphate;-   (R)-4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(1-methylpyrrolidin-3-yl)benzamide;-   (R)-4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methoxybenzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-chloro-benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethyl-benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(difluoromethoxy)benzoic    acid;-   6-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-4-methoxy-pyridine-3-carboxylic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-hydroxy-benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-fluoro-benzoic    acid;-   (2S)-2-amino-3-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]phenyl]-propanoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-1-methyl-2-morpholino-ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-hydroxy-N-(2-morpholinoethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-fluoro-1-piperidyl)ethyl]-2-methoxy-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-quinuclidin-4-yl-benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(quinuclidin-4-ylmethyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-quinuclidin-4-ylethyl)benzamide;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-(3-methoxy-4-methylsulfonyl-anilino)-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-(3-methoxy-4-methylsulfinyl-anilino)-4-pyridyl]oxy]-1-naphthyl]urea;-   1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-(2-morpholinoethylsulfonyl)anilino]-4-pyridyl]oxy]-1-naphthyl]urea;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(1-methyl-4-piperidyl)propyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-piperidyl)ethyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-N-(4-morpholinobutyl)benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-1-methyl-3-morpholino-propyl]benzamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-1-methyl-3-morpholino-propyl]benzamide;-   2-[5-tert-butyl-2-methoxy-3-[[4-[[2-[3-methoxy-4-[2-(1-oxo-1,4-thiazinan-4-yl)ethylcarbamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]carbamoylamino]-N-methylsulfonyl-anilino]ethyl    dihydrogen phosphate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphinic    acid;-   30    [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphonic    acid;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-phenyl]-methyl-phosphinic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzenesulfinic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(trifluoromethoxy)benzoic    acid;-   6-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-pyridine-3-carboxylic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethyl-benzoic    acid;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((3-morpholinopropyl)sulfonyl)phenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-morpholinoethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(3-morpholinopropyl)benzamide;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2H-tetrazol-5-yl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)benzenesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-cyclopropylpiperazin-1-yl)ethyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(piperidin-4-yl)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxybenzenesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-hydroxy-N-(3-morpholinopropyl)benzamide;-   4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2-oxopyridin-1    (2H)-yl)phenyl)amino)-pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;-   5-(tert-butyl)-N-(2-hydroxyethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;-   4-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)morpholine    4-oxide;-   7-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)heptanoic    acid;-   2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl    dihydrogen phosphate;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,6-dimethoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-2,6-dimethoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,2-bis(hydroxymethyl)propyl)-2-methoxybenzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-2,6-dimethoxybenzamide;-   N-(5-(tert-butyl)-3-(3-(4-((2-((4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide;-   4-((4-((4-(3-(5-(tert-butyl)-3-(2-hydroxyacetamido)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)benzamide;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinic    acid;-   (5-(tert-butyl)-3-(3-(4-((2-((4-((3-hydroxy-2,2-bis(hydroxymethyl)propyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxybenzoic    acid;-   2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)ethyl    dihydrogen phosphate;-   4-((4-((4-(3-(5-(tert-butyl)-3-(N-(2-hydroxyethyl)methylsulfonamido)-2-methoxyphenyl)ureido)    naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide;-   5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)-carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic    acid;-   diethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)phosphonate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethoxy-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-phenyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-2-methoxy-3-[methyl(methylsulfonyl)amino]phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   40    [4-[[4-[[4-[[5-tert-butyl-2-methoxy-3-(methylcarbamoyl)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methyl-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]pyrimidin-2-yl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-chloro-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)phenyl]-methyl-phosphinic    acid;-   ethyl    4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)phosphinate;-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)    ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl)(methyl)phosphinic    acid;-   ethyl    (4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[3-tert-butyl-5-(methanesulfonamido)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(trifluoromethyl)benzoic    acid;-   (2R)-2-amino-3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propanoic    acid;-   (2S)-2-amino-3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propanoic    acid;-   (2R)-2-amino-4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butanoic    acid;-   (2S)-2-amino-4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butanoic    acid;-   (2R)-2-amino-5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoic    acid;-   (2S)-2-amino-5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoic    acid;-   (2R)-2-amino-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]hexanoic    acid;-   (2R)-2-amino-7-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]heptanoic    acid;-   (2S)-2-amino-7-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]heptanoic    acid;-   (2S)-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]-2-(methylamino)hexanoic    acid;-   (2S)-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]-2-(dimethylamino)hexanoic    acid;-   (2R)-2-amino-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-5-oxo-pentanoic    acid;-   (2S)-2-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoic    acid;-   (2R)-2-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoic    acid;-   5-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-3-methoxy-pyridine-2-carboxylic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfanyl-benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfinyl-benzoic    acid;-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfonyl-benzoic    acid;-   2-[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]acetic    acid;-   2-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butoxy]acetic    acid;-   2-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butylamino]acetic    acid;-   3-[3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propylamino]propanoic    acid;-   4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethylamino]butanoic    acid;-   (2S)-2-amino-3-[4-[[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]methyl]-phenyl]propanoic    acid;-   (2R)-2-amino-3-[4-[[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]methyl]-phenyl]propanoic    acid;-   (2R)-2-amino-3-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]phenyl]-propanoic    acid;-   (4S)-4-amino-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-5-oxo-pentanoic    acid;-   (3S)-3-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoic    acid;-   (2S)-2-amino-6-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-6-oxo-hexanoic    acid;-   (2R)-2-amino-6-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-6-oxo-hexanoic    acid;-   (2S)-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-2-(methylamino)-5-oxo-pentanoic    acid; and-   (2S)-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-2-(dimethylamino)-5-oxo-pentanoic    acid,    or a pharmaceutically acceptable salt thereof.

Alternative embodiments of the invention that may be mentioned includethose in which the compound of formula I, Ia or Ib is as hereinbeforedefined, provided that it is not: (i) one compound selected from theabove list, or a pharmaceutically acceptable salt thereof; or (ii) anytwo or more compounds selected from the above list, or pharmaceuticallyacceptable salts thereof.

-   Examples of salts of compounds of formula I, Ia or Ib include all    pharmaceutically acceptable salts, such as, without limitation, acid    addition salts of strong mineral acids such as HCl, H₂SO₄ and HBr    salts (e.g. HCl or HBr salts) and addition salts of strong organic    acids such as methanesulfonic acid.

Particular salts of compounds of formula I, Ia or Ib that may bementioned include hydrochloric acid salts and, for those compoundscontaining one or more acidic functional groups (e.g. functional groupscomprising OH attached directly to a C(O), S(O)₁₋₂ or P(O) moiety),sodium, ammonium, calcium, magnesium, N-methylglucamine((2R,3R,4R,5S)-6-(methylamino)-hexane-1,2,3,4,5-pentol) or benethamine(N-benzyl-2-phenethylamine) salts (e.g. sodium or ammonium salts).

Particular hydrochloride salts that may be mentioned includehydrochloride salts of the following compounds:

-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxybenzoyl]amino]pentanoic    acid;-   2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)acetic    acid;-   4-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)butanoic    acid;-   (S)-1-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoyl)pyrrolidine-2-carboxylic    acid;-   3-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propanoic    acid;-   6-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoic    acid;-   4-((2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)amino)-4-oxobutanoic    acid;-   4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   7-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)heptanoic    acid; and-   4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-fluoro-benzoic    acid.

Particular dihydrochloride salts that may be mentioned includedihydrochloride salts of the following compounds:

-   (S)-2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-(1H-imidazol-4-yl)propanoic    acid;-   (S)-2-amino-6-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoic    acid; and-   (2S)-2-amino-3-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]phenyl]-propanoic    acid.

Particular sodium and ammonium salts that may be mentioned includesodium or ammonium (e.g. sodium, disodium, ammonium or diammonium) saltsof the following compounds:

-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid;-   4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxybenzoic    acid;-   (S)-2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-hydroxypropanoic    acid;-   N-((4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)sulfonyl)propionamide;-   2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethyl    dihydrogen phosphate;-   2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethoxy)ethyl    dihydrogen phosphate;-   2-((5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)-ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)amino)-2-oxoethyl    dihydrogen phosphate;-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinic    acid;-   2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)ethyl    dihydrogen phosphate;-   2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl    dihydrogen phosphate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)phenyl]-methyl-phosphinic    acid; and-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl)(methyl)phosphinic    acid.

Specific embodiments of the above-described compounds of formula I, Iaor Ib that may be mentioned include those in which R⁴:

-   (a) represents -Q⁴-P(O)(OR⁹)(R⁷) (e.g. —P(O)(OR⁹)(R⁷)); or-   (b) does not represent -Q⁴-P(O)(OR⁹)(R⁷).

Thus, further embodiments of the invention that may be mentioned includethose in which either

-   (i) the compound of formula I, Ia or Ib represents, or-   (ii) the compound of formula I, Ia or Ib is as hereinbefore defined,    provided that is does not represent    a compound selected from the list comprising:-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphinic    acid;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphonic    acid;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinic    acid;-   diethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)phosphonate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethoxy-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-phenyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-2-methoxy-3-[methyl(methylsulfonyl)amino]phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-2-methoxy-3-(methylcarbamoyl)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methyl-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]pyrimidin-2-yl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)phosphinate;-   [[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-chloro-phenyl]-methyl-phosphinic    acid;-   ethyl    (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)phenyl]-methyl-phosphinic    acid;-   ethyl    4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)phosphinate;-   (4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl)(methyl)phosphinic    acid; and-   ethyl    (4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate;-   [4-[[4-[[4-[[3-tert-butyl-5-(methanesulfonamido)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinic    acid,    or a pharmaceutically acceptable salt thereof.

In particular, further embodiments of the invention that may bementioned include those in which the salt of the compound of formula I,Ia or Ib either (i) represents; or (ii) does not represent a sodium orammonium salt of(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinicacid.

Still further embodiments of the invention that may be mentioned includethose in which either

-   (i) the compound of formula I, Ia or Ib represents, or-   (ii) the compound of formula I, Ia or Ib is as hereinbefore defined,    provided that is does not represent    4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid,    or a pharmaceutically acceptable salt thereof (e.g. a hydrochloride,    sodium, calcium, magnesium or ammonium salt thereof).

The compound4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid may also be known by the chemical name4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoicacid.

References herein to a compound of the invention (a compound of formulaI, Ia or Ib) are intended to include references to the compound and toall pharmaceutically acceptable salts, solvates, isotopic derivativesand/or tautomers of said compound, unless the context specificallyindicates otherwise. In this respect, solvates that may be mentionedinclude hydrates.

The compounds of the invention (compounds of formula I, Ia or Ib) arep38 MAP kinase inhibitors (especially of the alpha subtype) and aretherefore useful in medicine, in particular for the treatment ofinflammatory diseases. Further aspects of the invention that may bementioned therefore include the following.

-   (a) A pharmaceutical formulation comprising a compound of formula I,    Ia or Ib, as hereinbefore defined, or pharmaceutically acceptable    salt thereof, in admixture with a pharmaceutically acceptable    adjuvant, diluent or carrier.-   (b) A combination product comprising    -   (A) a compound of formula I, Ia or Ib, as hereinbefore defined,        or pharmaceutically acceptable salt thereof, and    -   (B) another therapeutic agent,-    wherein each of components (A) and (B) is formulated in admixture    with a pharmaceutically-acceptable adjuvant, diluent or carrier.-    In this aspect of the invention, the combination product may be    either a single (combination) pharmaceutical formulation or a    kit-of-parts.-    Thus, this aspect of the invention encompasses a pharmaceutical    formulation including a compound of formula I, Ia or Ib, as    hereinbefore defined, or pharmaceutically acceptable salt thereof,    and another therapeutic agent, in admixture with a pharmaceutically    acceptable adjuvant, diluent or carrier (which formulation is    hereinafter referred to as a “combined preparation”).-    It also encompasses a kit of parts comprising components:    -   (i) a pharmaceutical formulation including a compound of formula        I, Ia or Ib, as hereinbefore defined, or pharmaceutically        acceptable salt thereof, in admixture with a pharmaceutically        acceptable adjuvant, diluent or carrier; and    -   (ii) a pharmaceutical formulation including another therapeutic        agent, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier,-    which components (i) and (ii) are each provided in a form that is    suitable for administration in conjunction with the other.-    Component (i) of the kit of parts is thus component (A) above in    admixture with a pharmaceutically acceptable adjuvant, diluent or    carrier. Similarly, component (ii) is component (B) above in    admixture with a pharmaceutically acceptable adjuvant, diluent or    carrier.-   (c) A process for preparing the pharmaceutical formulation of    aspect (a) above, said process comprising the step of admixing the    compound of formula I, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, with a pharmaceutically    acceptable adjuvant, diluent or carrier.-    Embodiments of this aspect of the invention that may be mentioned    include those in which the pharmaceutically acceptable adjuvant,    diluent or carrier is a topically acceptable adjuvant, diluent or    carrier (and/or wherein the process is for preparing a topical    pharmaceutical formulation, i.e. a pharmaceutical formulation that    is adapted for topical administration).-   (d) A compound of formula I, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, for use in medicine (or    for use as a medicament or as a pharmaceutical).-   (e) A compound of formula I, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, or a pharmaceutical    formulation or combination product as defined in connection with    aspect (a) or (b) of the invention, for use in the treatment or    prevention of an inflammatory disease.-   (f) The use of    -   a compound of formula I, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention, for the        preparation of a medicament for the treatment or prevention of        an inflammatory disease.-   (g) A method of treating or preventing an inflammatory disease, said    method comprising administering to a subject an effective amount of    -   a compound of formula I, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.-   (h) A method of sensitizing a subject to the anti-inflammatory    effects of a corticosteroid, said method comprising administering to    the subject an effective amount of    -   a compound of formula I, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.-    Embodiments of this aspect of the invention that may be mentioned    include those in which the subject is one who has become refractory    to the anti-inflammatory effects of a corticosteroid.

References herein to “preventing an inflammatory disease” includereferences to preventing (or reducing the likelihood of) the recurrenceof an inflammatory disease in a subject who has previously suffered fromsuch a disease (e.g. a subject who has previously received treatment forthat disease, for example treatment according to the method described in(g) above).

Thus, still further aspects of the invention that may be mentionedinclude the following.

-   (i) A compound of formula I, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, or a pharmaceutical    formulation or combination product as defined in connection with    aspect (a) or (b) of the invention, for use in reducing the    likelihood of the recurrence of an inflammatory disease in a subject    who has previously received treatment for that disease (e.g.    treatment with a compound of formula I, Ia or Ib, as hereinbefore    defined, or pharmaceutically acceptable salt thereof, or a    pharmaceutical formulation or combination product as defined in    connection with aspect (a) or (b) of the invention).-   (j) The use of    -   a compound of formula I, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention,-    for the preparation of a medicament for reducing the likelihood of    the recurrence of an inflammatory disease in a subject who has    previously received treatment for that disease (e.g. treatment with    a compound of formula I, Ia or Ib, as hereinbefore defined, or    pharmaceutically acceptable salt thereof, or a pharmaceutical    formulation or combination product as defined in connection with    aspect (a) or (b) of the invention).-   (k) A method of reducing the likelihood of the recurrence of an    inflammatory disease in a subject who has previously received    treatment for that disease (e.g. treatment with a compound of    formula I, Ia or Ib, as hereinbefore defined, or pharmaceutically    acceptable salt thereof, or a pharmaceutical formulation or    combination product as defined in connection with aspect (a) or (b)    of the invention), said method comprising administering to said    subject an effective amount of    -   a compound of formula I, Ia or Ib, as hereinbefore defined, or        pharmaceutically acceptable salt thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.

Formulations

In relation to aspects (a) and (b) above, diluents and carriers that maybe mentioned include those suitable for parenteral, oral, topical,mucosal and rectal administration.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may be prepared e.g. for parenteral, subcutaneous,intramuscular, intravenous, intra-articular, intravitreous, periocular,retrobulbar, subconjunctival, sub-Tenon, topical ocular orperi-articular administration, particularly in the form of liquidsolutions, emulsions or suspensions; for oral administration,particularly in the form of tablets or capsules, and especiallyinvolving technologies aimed at furnishing colon-targeted drug release(Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258); fortopical e.g. pulmonary or intranasal administration, particularly in theform of powders, nasal drops or aerosols and transdermal administration;for topical ocular administration, particularly in the form ofsolutions, emulsions, suspensions, ointments, implants/inserts, gels,jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser,H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287); for ocularadministration, particularly in the form of biodegradable andnon-biodegradable implants, liposomes and nanoparticles (Thrimawithana,T. R. et al. Drug Discov. Today 2011, 16 (5/6), 270-277); for mucosaladministration e.g. to buccal, sublingual or vaginal mucosa, and forrectal administration e.g. in the form of a suppository or enema.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may conveniently be administered in unit dosage form andmay be prepared by any of the methods well-known in the pharmaceuticalart, for example as described in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., (1985). Formulations forparenteral administration may contain as excipients sterile water orsaline, alkylene glycols such as propylene glycol, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, hydrogenatednaphthalenes and the like. Formulations for nasal administration may besolid and may contain excipients, for example, lactose or dextran, ormay be aqueous or oily solutions for use in the form of nasal drops ormetered sprays. For buccal administration, typical excipients includesugars, calcium stearate, magnesium stearate, pregelatinised starch, andthe like.

Pharmaceutical formulations and combination products suitable for oraladministration may comprise one or more physiologically compatiblecarriers and/or excipients and may be in solid or liquid form. Tabletsand capsules may be prepared with binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrrolidone;fillers, such as lactose, sucrose, corn starch, calcium phosphate,sorbitol, or glycine; lubricants, such as magnesium stearate, talc,polyethylene glycol, or silica; and surfactants, such as sodium laurylsulfate. Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose, sugarsyrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifyingagents such as lecithin, or acacia; vegetable oils such as almond oil,coconut oil, cod liver oil, or peanut oil; preservatives such asbutylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).Liquid compositions may be encapsulated in, for example, gelatin toprovide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules. Such two-piece hard shellcapsules may be made from, for example, gelatin or hydroxylpropylmethylcellulose (HPMC).

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

A compound of the invention may be administered topically (e.g. to thelung, eye or intestines). Thus, embodiments of aspects (a) and (b) abovethat may be mentioned include pharmaceutical formulations andcombination products that are adapted for topical administration. Suchformulations include those in which the excipients (including anyadjuvant, diluent and/or carrier) are topically acceptable.

Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoroethane (propellant 114), and dichlorodifluoromethane(propellant 12).

Suitable HFC propellants include tetrafluoroethane (HFC-134a) andheptafluoropropane (HFC-227). The propellant typically comprises 40% to99.5% e.g. 40% to 90% by weight of the total inhalation composition. Theformulation may comprise excipients including co-solvents (e.g. ethanol)and surfactants (e.g. lecithin, sorbitan trioleate and the like). Otherpossible excipients include polyethylene glycol, polyvinylpyrrolidone,glycerine and the like. Aerosol formulations are packaged in canistersand a suitable dose is delivered by means of a metering valve (e.g. assupplied by Bespak, Valois or 3M or alternatively by Aptar, Coster orVari).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser e.g. one that can behand-held and portable or for home or hospital use (i.e. non-portable).The formulation may comprise excipients such as water, buffers, tonicityadjusting agents, pH adjusting agents, surfactants and co-solvents.Suspension liquid and aerosol formulations (whether pressurised orunpressurised) will typically contain the compound of the invention infinely divided form, for example with a D₅₀ of 0.5-10 μm e.g. around 1-5μm. Particle size distributions may be represented using D₁₀, D₅₀ andD₉₀ values. The D₅₀ median value of particle size distributions isdefined as the particle size in microns that divides the distribution inhalf. The measurement derived from laser diffraction is more accuratelydescribed as a volume distribution, and consequently the D₅₀ valueobtained using this procedure is more meaningfully referred to as a Dv₅₀value (median for a volume distribution). As used herein Dv values referto particle size distributions measured using laser diffraction.Similarly, D₁₀ and D₉₀ values, used in the context of laser diffraction,are taken to mean Dv₁₀ and Dv₉₀ values and refer to the particle sizewhereby 10% of the distribution lies below the D₁₀ value, and 90% of thedistribution lies below the D₉₀ value, respectively.

Topical administration to the lung may also be achieved by use of adry-powder formulation. A dry powder formulation will contain thecompound of the disclosure in finely divided form, typically with a massmean aerodynamic diameter (MMAD) of 1-10 μm or a D₅₀ of 0.5-10 μm e.g.around 1-5 μm. Powders of the compound of the invention in finelydivided form may be prepared by a micronization process or similar sizereduction process. Micronization may be performed using a jet mill suchas those manufactured by Hosokawa Alpine. The resultant particle sizedistribution may be measured using laser diffraction (e.g. with aMalvern Mastersizer 2000S instrument). The formulation will typicallycontain a topically acceptable diluent such as lactose, glucose ormannitol (preferably lactose), usually of large particle size e.g. anMMAD of 50 μm or more, e.g. 100 μm or more or a D₅₀ of 40-150 μm. Asused herein, the term “lactose” refers to a lactose-containingcomponent, including α-lactose monohydrate, β-lactose monohydrate,α-lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactosecomponents may be processed by micronization, sieving, milling,compression, agglomeration or spray drying. Commercially available formsof lactose in various forms are also encompassed, for example Lactohale®(inhalation grade lactose; DFE Pharma), InhaLac® 70 (sieved lactose fordry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose®(sieved inhalation grade lactose; DFE Pharma) products. In oneembodiment, the lactose component is selected from the group consistingof α-lactose monohydrate, α-lactose anhydrous and amorphous lactose.Preferably, the lactose is α-lactose monohydrate.

Dry powder formulations may also contain other excipients such as sodiumstearate, calcium stearate or magnesium stearate.

A dry powder formulation is typically delivered using a dry powderinhaler (DPI) device. Examples of dry powder delivery systems includeSPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Furtherexamples of dry powder delivery systems include ECLIPSE, NEXT,ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER,MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER,TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler,MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER,GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

In one embodiment a compound of the present invention is provided in amicronized dry powder formulation, for example further comprisinglactose of a suitable grade optionally together with magnesium stearate,filled into a single dose device such as AEROLISER or filled into amulti dose device such as DISKUS.

The compounds of the present invention may also be administeredrectally, for example in the form of suppositories or enemas, whichinclude aqueous or oily solutions as well as suspensions and emulsions.Such compositions are prepared following standard procedures, well knownby those skilled in the art. For example, suppositories can be preparedby mixing the active ingredient with a conventional suppository basesuch as cocoa butter or other glycerides, e.g. Suppocire. In this case,the drug is mixed with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperature andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

Generally, for compositions intended to be administered topically to theeye in the form of eye drops or eye ointments, the total amount of theinhibitor will be about 0.0001 to less than 4.0% (w/w).

Preferably, for topical ocular administration, the compositionsadministered according to the present invention will be formulated assolutions, suspensions, emulsions and other dosage forms. Aqueoussolutions are generally preferred, based on ease of formulation, as wellas a patient's ability to administer such compositions easily by meansof instilling one to two drops of the solutions in the affected eyes.However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds that are sparingly soluble inwater.

The compositions administered according to the present invention mayalso include various other ingredients, including, but not limited to,tonicity agents, buffers, surfactants, stabilizing polymer,preservatives, co-solvents and viscosity building agents. Preferredpharmaceutical compositions of the present invention include theinhibitor with a tonicity agent and a buffer. The pharmaceuticalcompositions of the present invention may further optionally include asurfactant and/or a palliative agent and/or a stabilizing polymer.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, simple sugars, such as dextrose,fructose, galactose, and/or simply polyols, such as the sugar alcoholsmannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, andhydrogenated starch hydrolysates may be added to the composition toapproximate physiological tonicity. Such an amount of tonicity agentwill vary, depending on the particular agent to be added. In general,however, the compositions will have a tonicity agent in an amountsufficient to cause the final composition to have an ophthalmicallyacceptable osmolality (generally about 150-450 mOsm, preferably 250-350mOsm and most preferably at approximately 290 mOsm). In general, thetonicity agents of the invention will present in the range of 2 to 5%w/w (e.g. 2 to 4% w/w). Preferred tonicity agents of the inventioninclude the simple sugars or the sugar alcohols, such as D-mannitol.

An appropriate buffer system (e.g. sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed.Preferably however, the buffer will be chosen to maintain a target pHwithin the range of pH 5 to 8, and more preferably to a target pH of pH5 to 7, or a target pH of 6.5 to 7.6.

Surfactants may optionally be employed to deliver higher concentrationsof inhibitor. The surfactants function to solubilise the inhibitor andstabilise colloid dispersion, such as micellar solution, microemulsion,emulsion and suspension. Examples of surfactants which may optionally beused include polysorbate, poloxamer, polyoxyl 40 stearate, polyoxylcastor oil, tyloxapol, triton, and sorbitan monolaurate. Preferredsurfactants to be employed in the invention have ahydrophile/lipophile/balance “HLB” in the range of 12.4 to 13.2 and areacceptable for ophthalmic use, such as TritonX114 and tyloxapol.

For example, a formulation of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, or pharmaceutically acceptable salt thereof, for topical ocularadministration may comprise:

-   (a) water;-   (b) a surfactant (e.g. polyoxyl 40 stearate);-   (c) a tonicity agent (e.g. mannitol); and-   (d) an appropriate buffer system (e.g. a phosphate buffer containing    a mixture of monobasic dihydrogen phosphate and dibasic monohydrogen    phosphate) chosen to maintain a target pH within the range from 6.5    to 8.

In such topical ocular formulations, one or more (e.g. all) of thefollowing may apply:

-   (i)    4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoic    acid is present at a concentration in the range from 0.001 to 20    mg/mL (e.g. from 0.01 to 10 mg/mL, 0.1 to 2 mg/mL or, particularly,    1 mg/mL);-   (ii) the surfactant (e.g. polyoxyl 40 stearate) is present at from 1    to 10% w/w (e.g. from 2 to 5% w/w, such as from 2.5 to 4% w/w or,    particularly, 3% w/w);-   (iii) the tonicity agent (e.g. mannitol) is present at from 1 to 15%    w/w (e.g. from 2 to 10% w/w, such as from 3 to 6% w/w or,    particularly, 4.5% w/w);-   (iv) the buffer system used as a component of the formulation is an    aqueous phosphate buffer (e.g. a 10 mM aqueous phosphate buffer)    chosen to maintain a target pH within the range from 6.5 to 8.0    (e.g. within the range from 7.0 to 7.8 or, particularly, from 7.2 to    7.6).

Additional agents that may be added to the ophthalmic compositions ofthe present invention are demulcents which function as a stabilisingpolymer. The stabilizing polymer should be an ionic/charged example withprecedence for topical ocular use, more specifically, a polymer thatcarries negative charge on its surface that can exhibit a zeta-potentialof (−) 10-50 mV for physical stability and capable of making adispersion in water (i.e. water soluble). A preferred stabilisingpolymer of the invention would be polyelectrolyte, or polyelectrolytesif more than one, from the family of cross-linked polyacrylates, such ascarbomers, polycarbophil and Pemulen®, specifically Carbomer 974p(polyacrylic acid), at 0.1-0.5% w/w.

Other compounds may also be added to the ophthalmic compositions of thepresent invention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily, vinyl polymers and acrylic acid polymers.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1,or other agents known to those skilled in the art. Such preservativesare typically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The medical practitioner, or other skilled person, will be able todetermine a suitable dosage for the compounds of the invention, andhence the amount of the compound of the invention that should beincluded in any particular pharmaceutical formulation (whether in unitdosage form or otherwise).

Embodiments of the invention that may be mentioned in connection withthe combination products described at (b) above include those in whichthe other therapeutic agent is one or more therapeutic agents that areknown by those skilled in the art to be suitable for treatinginflammatory diseases (e.g. the specific diseases mentioned below).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   steroids (e.g. budesonide, beclomethasone dipropionate,        fluticasone propionate, mometasone furoate, fluticasone furoate;        a further example is ciclesonide);    -   beta agonists, particularly beta2 agonists (e.g. terbutaline,        salbutamol, salmeterol, formoterol; further examples are        vilanterol, olodaterol, reproterol and fenoterol); and    -   xanthines (e.g. theophylline).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   muscarinic antagonists (e.g. tiotropium, umeclidinium,        glycopyrronium, aclidinium and daratropium, any of these for        example as the bromide salt); and    -   phosphodiesterase inhibitors.

Further, for the treatment of gastrointestinal disorders (such asCrohn's disease or ulcerative colitis), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or balsalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol or golimumab); anti-IL12/IL23 antibodies (e.g.        ustekinumab) or small molecule IL12/IL23 inhibitors (e.g.        apilimod);    -   anti-α417 antibodies (e.g. vedolizumab);    -   toll-like receptor (TLR) blockers (e.g. BL-7040; Avecia        (Cambridge, UK));    -   MAdCAM-1 blockers (e.g. PF-00547659);    -   antibodies against the cell adhesion molecule a4-integrin (e.g.        natalizumab);    -   antibodies against the IL2 receptor a subunit (e.g. daclizumab        or basiliximab); anti-Smad7 antibodies (e.g. mongersen (GED0301;        all-P-ambo-2′-deoxy-P-thioguanylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-Pthiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-5-methyl-P-thiocytidylyl-(3′→5′)-2′-deoxy-Pthioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-Pthioadenylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxycytidine));    -   sphingosine 1-phosphate receptor 1 (S1P1) modulators (e.g.        ozanimod        ((S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile),        amiselimod (MT1303;        2-amino-2-{2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl}propane-1,3-diol)        or APD334        (2-[7-[4-cyclopentyl-3-(trifluoromethyl)benzyloxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3(R)-yl]acetic        acid));    -   JAK inhibitors (e.g. tofacitinib, baricitinib        (1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile),        filgotinib        (N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide),        peficitinib        (4-(((1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide)        or R348 (see, for example, US 2014/0206708));    -   STAT3 inhibitors (e.g. TAK-114;        (3E)-1-methyl-3-(2-oxo-1H-indol-3-ylidene)indol-2-one);    -   receptor-interacting protein-1 (RIP1) kinase inhibitors (e.g.        GSK2982772);    -   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g. tetomilast);    -   HMPL-004;    -   probiotics;    -   microbiome modulators (e.g. SGM1019);    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071)        (e.g. for the treatment of gastrointestinal disorders (such as        Crohn's disease or ulcerative colitis), the other therapeutic        agent may be, for example, one or more agents selected from the        list comprising:    -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or balsalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol or golimumab);    -   anti-IL12/IL23 antibodies (e.g. ustekinumab) or small molecule        IL12/IL23 inhibitors (e.g. apilimod);    -   anti-α4β7 antibodies (e.g. vedolizumab);    -   MAdCAM-1 blockers (e.g. PF-00547659);    -   antibodies against the cell adhesion molecule a4-integrin (e.g.        natalizumab);    -   antibodies against the IL2 receptor a subunit (e.g. daclizumab        or basiliximab);    -   JAK3 inhibitors (e.g. tofacitinib or R348);    -   Syk inhibitors and prodrugs thereof (e.g. fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g. tetomilast);    -   HMPL-004;    -   probiotics;    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071)).

For the treatment of eye disorders (such as uveitis andkeratoconjunctivitis sicca (dry eye)), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   glucocorticoid agonists (e.g. mapracorat);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   adenosine A3 receptor agonists (e.g. CF-101);    -   lifitegrast;    -   IL1 blockers (e.g. EBI-005; Hou et al. PNAS 2013, 110(10),        3913-3918); RGN-259 (Thymosin β4);    -   SI-614;    -   OTX-101;    -   JNK inhibitors (e.g. XG-104);    -   MAP kinase signalling inhibitors (e.g. DA-6034;        {[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxochromen-7-yl]oxy}acetic        acid);    -   mucin stimulators (e.g. rebamipide;        2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic        acid);    -   MIM-D3 (Tavilermide; see, for example, US 2013/0345395);    -   JAK inhibitors (e.g. tofacitinib, baricitinib        (1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile),        filgotinib        (N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide),        peficitinib        (4-(((1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide)        or R348 (see, for example, US 2014/0206708)); and    -   protein kinase C inhibitors (e.g. AEB-071).        (e.g. for the treatment of eye disorders (such as uveitis and        keratoconjunctivitis sicca (dry eye)), the other therapeutic        agent may be, for example, one or more agents selected from the        list comprising:    -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   glucocorticoid agonists (e.g. mapracorat);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   adenosine A3 receptor agonists (e.g. CF-101);    -   lifitegrast;    -   JAK3 inhibitors (e.g. tofacitinib or R348); and    -   protein kinase C inhibitors (e.g. AEB-071)).

In particular embodiments, for the treatment of eye disorders (such asuveitis and keratoconjunctivitis sicca (dry eye)), the other therapeuticagent may be, for example, one or more agents selected from the listcomprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g. infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g. secukinumab);    -   mTOR inhibitors (e.g. sirolimus);    -   VGX-1027;    -   JAK inhibitors (e.g. tofacitinib, baricitinib, filgotinib,        peficitinib or R348) (e.g. JAK3 inhibitors such as tofacitinib        or R348); and    -   protein kinase C inhibitors (e.g. AEB-071).

Medical Uses

The compounds of the invention may be used as monotherapies forinflammatory diseases, or in combination therapies for such diseases.

Thus, embodiments of aspects (e) to (g) above that may be mentionedinclude those in which the compound of formula I, Ia or Ib (orpharmaceutically acceptable salt thereof) is the sole pharmacologicallyactive ingredient utilised in the treatment.

However, in other embodiments of aspects (e) to (g) above, the compoundof formula I, Ia or Ib (or pharmaceutically acceptable salt thereof) isadministered to a subject who is also administered one or more othertherapeutic agents (e.g. wherein the one or more other therapeuticagents are as defined above in connection with combination products).

When used herein, the term “inflammatory disease” specifically includesreferences to any one or more of the following:

-   (i) lung diseases or disorders having an inflammatory component,    such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis,    idiopathic pulmonary fibrosis or, particularly, COPD (including    chronic bronchitis and emphysema), asthma or pediatric asthma;-   (ii) skin diseases or disorders having an inflammatory component,    such as atopic dermatitis, allergic dermatitis, contact dermatitis    or psoriasis;-   (iii) nasal diseases or disorders having an inflammatory component,    such as allergic rhinitis, rhinitis or sinusitis;-   (iv) eye diseases or disorders having an inflammatory component,    such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic    retinopathy, macular oedema (including diabetic macular oedema),    central retinal vein occlusion (CRVO), dry and/or wet age related    macular degeneration (AMD), post-operative cataract inflammation,    or, particularly, keratoconjunctivitis sicca (dry eye, also known as    xerophthalmia), uveitis (including posterior, anterior and pan    uveitis), corneal graft and limbal cell transplant rejection; and-   (v) gastrointestinal diseases or disorders having an inflammatory    component, such as gluten sensitive enteropathy (coeliac disease),    eosinophilic esophagitis, intestinal graft versus host disease or,    particularly, Crohn's disease or ulcerative colitis.

References herein to diseases having an inflammatory component includereferences to diseases that involve inflammation, whether or not thereare other (non-inflammatory) symptoms or consequences of the disease.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I (e.g. a compoundof formula Ib in which R^(1A) and R^(5a) both represent methoxy, R^(1B)represents —NHS(O)₂CH₃, R^(1D) represents tert-butyl, X¹ and X² bothrepresent CH, R^(5b) represents H and R⁴ represents —CO₂H) which processcomprises:

(a) reaction of a compound of formula II

with a compound of formula III,

wherein one of Z¹ and Z² is a structural fragment of formula IV

and the other of Z¹ and Z² is a structural fragment of formula V

where R^(1A) to R^(1E), R² to R⁴, R^(5a), L and X¹ to X³ are ashereinbefore defined (e.g. X³ represents CR^(5b) and R^(1A) to R^(1E),R² to R⁴, R^(5a), R^(5b), L and X² are as hereinbefore defined), forexample under conditions known to those skilled in the art, for exampleat a temperature from ambient (e.g. 15 to 30° C.) to about 110° C. inthe presence of a suitable organic solvent (e.g. a polar aprotic solventsuch as DMF, THF, 1,4-dioxane, or mixtures thereof);(b) reaction of a compound of formula IIa,

wherein Z¹ is as defined above, with a suitable azide-forming agent(i.e. a suitable source of a leaving group and activated azide ion, suchas diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30,2151-2157) under conditions known to those skilled in the art, such asat sub-ambient to ambient temperature (e.g. from an initial temperatureof about −5 to 5° C. to ambient temperature post-reaction) in thepresence of an amine base (e.g. triethylamine or a sterically hinderedbase such as N,N-diisopropylethylamine) and a suitable organic solvent(e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or mixturesthereof), which reaction is followed, without isolation, by thermalrearrangement (e.g. under heating) of the intermediate acyl azide (offormula Z¹—C(O)—N₃) e.g. at ambient temperature (such as from 15 to 30°C.) to provide, in situ, a compound of formula II, which compound isthen reacted with a compound of formula III, as defined above, toprovide the compound of formula I;(c) reaction of a compound of formula IIb,

wherein LG¹ represents a suitable leaving group (e.g. imidazolyl,chloro, or aryloxy, such as phenoxy) and Z¹ is as defined above, with acompound of formula III, as defined above, for example under conditionsknown to those skilled in the art, such as at ambient temperature (e.g.from ambient to 80° C.), optionally in the presence of an amine base(e.g. triethylamine or a sterically hindered base likeN,N-diisopropylethylamine) and a suitable organic solvent (e.g. anaprotic solvent, such as dichloromethane or an ester such as isopropylacetate);(d) reaction of a compound of formula VI,

wherein LG² represents a suitable leaving group (e.g. a halo group suchas chloro or bromo) and R^(1A) to R^(1E), R², R³ and X¹ are ashereinbefore defined with a compound of formula VII,

wherein R⁴, R^(5a), L, X² and X³ are as hereinbefore defined (e.g. X³represents CR^(5b) and R⁴, R^(5a), R^(5b), L and X² are as hereinbeforedefined), for example under conditions known to those skilled in the art(e.g. as described in J. Am. Chem. Soc. 2011, 133, 15686-15696), such asat elevated temperature (e.g. from 50 to 110° C.) in the presence of asuitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF,1,4-dioxane, or mixtures thereof) and, optionally, an acidic catalyst(e.g. a sulfonic acid such as para-toluenesulfonic acid);(e) for compounds of formula I in which R⁴ represents

-   -   —S(O)₁₋₂—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   —S(O)₁₋₂—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a),    -   —S(O)₁₋₂R^(6b),    -   which C₁₋₅ alkylene group is optionally substituted as described        above,    -   oxidation of a corresponding compound of formula I in which,        respectively, R⁴ represents    -   —S—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   —S—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a),    -   —S—R^(6b),    -   which C₁₋₅ alkylene group is optionally substituted as described        above,    -   wherein R^(6a) to R^(6d) are as hereinbefore defined, for        example under conditions known to those skilled in the art (e.g.        at 0 to 25° C. in the presence of a suitable solvent (such as        dichloromethane, methanol or a mixture thereof) and a peracid,        such as meta-chloroperbenzoic acid);        (f) for compounds of formula I in which R⁴ represents    -   -Q^(1a)-NR⁸—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q^(2a)-NR⁸—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   -Q^(3a)-NR⁸—[C₁₋₄ alkylene]₀₋₁-Het³,    -   which C₁₋₅ alkylene and Het³ groups are optionally substituted        as described above, and wherein Q^(1a), Q^(2a) and Q^(3a)        represent C(O) or S(O)₂, reaction of a compound of formula VIIa,

wherein Q^(x) represents —[C₁₋₄ alkylene]₀₋₁C(O)OR^(4′) or —S(O)₂-LG²(e.g. Q^(x) represents —C(O)OR^(4′) or —S(O)₂-LG²), R^(4′) represents Hor a C₁₋₄ alkyl group (e.g. a C₄ alkyl group or a C₁₋₃ alkyl group, suchas methyl) and R^(1A) to R^(1E), R², R³, R^(5a), L, X¹ to X³ and LG² areas hereinbefore defined (e.g. X³ represents CR^(5b) and R^(1A) toR^(1E), R², R³, R^(5a), R^(5b), L, X¹, X² and LG² are as hereinbeforedefined), with a compound of formula VIIb, VIIc or VIId,

HNR⁸—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)  VIIb

HNR⁸—C(R^(6c))(R^(6d))—[C₁₋₅alkylene]-R^(6a1) or  VIIc

HNR⁸—[C₁₋₄alkylene]₀₋₁-Het³  VIId

which C₁₋₅ alkylene and Het³ groups are optionally substituted asdescribed above, wherein R^(6c), R^(6d), R⁸ and Het³ are as hereinbeforedefined, and R^(6a1) takes the same definition as R^(6a) above, exceptthat CO₂H is only present in protected form (e.g. as C(O)O—C₁₋₄ alkyl),for example under conditions known to those skilled in the art, such as(i) when R^(4′) represents a C₁₋₃ alkyl group, reaction at ambienttemperature in the presence of a suitable Lewis acidic catalyst (e.g. atrialkyl aluminium reagent such as trimethylaluminium) and an aproticorganic solvent (e.g. THF) or (ii) when R^(4′) represents H, reaction inthe presence of a tertiary amine base (e.g. a trialkylamine such astriethylamine or diisopropylethylamine or a cyclic amine such asN-methylpyrrolidine or N-methylmorpholine), an amide (peptide) couplingreagent (e.g. T3P, HATU, CDI, BOP, PyBOP, HOAt, HOBt or a carbodiimidesuch as DCC or diisopropylcarbodiimide) and an aprotic organic solvent(e.g. a chlorinated solvent such as DCM, an ester such as ethyl acetate,an amide of dimethylamine such as DMF, or a mixture of any suchsolvents), followed, if necessary, by deprotection of R^(6a1) when thatgroup represents C(O)O—C₁₋₄ alkyl;(g) for compounds of formula I in which R⁴ represents—S(O)₂—N(R^(7b))R^(7c), reaction of a compound of formula VIIa, asdefined above, in which Q^(x) represents —S(O)₂-LG² with a compound offormula HN(R^(7b))R^(7c), wherein R^(7b) and R^(7c) are as definedabove, for example under conditions known to those skilled in the art(e.g. conditions as described at (f) above);(h) for compounds of formula I in which R^(1B) represents—C(O)NR^(X)R^(Y), reaction of a compound of formula Vile,

wherein R^(1A), R^(X1), R^(1D), R^(1E), R² to R⁴, R^(5a), L and X¹ to X³are as hereinbefore defined (e.g. X³ represents CR^(5b) and R^(1A),R^(1C), R^(1D), R^(1E), R² to R⁴, R^(5a), R^(5b), L, X¹ and X² are ashereinbefore defined) and R^(X′) represents H or C₁₋₄ alkyl, with acompound of formula VIIf,

wherein R^(X) and R^(Y) are as hereinbefore defined, under conditionsknown to those skilled in the art, for example

-   -   when R^(X′) represents H, reaction in the presence of a suitable        solvent, a base (e.g. triethylamine or        N,N-diisopropylethylamine) and an amide (peptide) coupling        reagent, such as HATU, CDI, N,N′-dicyclohexylcarbodiimide,        N,N′-diisopropylcarbodiimide BOP or PyBOP, optionally in        combination with an activated ester-forming agent such as HOBt        or 1-hydroxy-7-azabenzotriazole,    -   when R^(X′) represents H, conversion of the carboxylic acid to        an acid halide (e.g. by reaction with a halogenating agent such        as thionyl chloride), followed by reaction with the compound of        formula (XI) in the presence of a suitable solvent and a base        (e.g. triethylamine or N,N-diisopropylethylamine), or    -   when R^(X′) represents C₁₋₄ alkyl (e.g. methyl), reaction in the        presence of a trialkylaluminum (e.g. trimethylaluminium) and an        aprotic solvent (e.g. THF);        (i) for compounds of formula I in which    -   R^(1A) represents C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, which latter four groups are substituted by —OP(O)(OH)₂        and are optionally further substituted by one or more        substituents selected from C₁₋₂ alkyl, halo, hydroxy, and C₁₋₂        alkoxy,    -   R^(X) and/or R^(X1) represents C₁₋₆ alkyl substituted by        —OP(O)(OH)₂ and optionally further substituted by one or more        substituents selected from halo, hydroxy and C₁₋₂ alkoxy,    -   R^(Y), R^(Y1) and/or R^(Y2) independently represent C₁₋₆ alkyl,        C₃₋₇ cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six        groups are substituted by —OP(O)(OH)₂ and are optionally further        substituted by one or more substituents selected from C₁₋₂        alkyl, halo, hydroxy, C₁₋₂ alkoxy, C(O)OH, C(O)O—(C₁₋₄ alkyl)        and —N(R^(a))(R^(b)), and which Het² group is optionally further        substituted with one or more oxo groups,    -   R^(1D) represents C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇        cycloalkyl, phenyl, Het¹ or Het², which latter seven groups are        substituted by —OP(O)(OH)₂ and are optionally further        substituted by one or more substituents selected from C₁₋₂        alkyl, halo, cyano, hydroxy and C₁₋₂ alkoxy;    -   R⁴ represents —CH₂OP(O)(OH)₂,    -   R^(6b) represents C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, Het¹ or        Het², which latter five groups are substituted by —OP(O)(OH)₂        and are optionally further substituted by one or more        substituents selected from halo, hydroxy, C₁₋₃ alkyl, C₁₋₃        alkoxy, —C₁₋₃ alkylene-R^(6e) and CO₂H,    -   R^(6e) represents —OP(O)(OH)₂ or    -   R^(7a) represents P(O)(OH)₂,        reaction of a hydroxy group on a corresponding compound of        formula I in which, respectively,    -   R^(1A) represents C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, which latter four groups are substituted by hydroxy and        are optionally further substituted by one or more substituents        selected from C₁₋₂ alkyl, halo, hydroxy, and C₁₋₂ alkoxy,    -   R^(X) and/or R^(X1) represents C₁₋₆ alkyl substituted by hydroxy        and optionally further substituted by one or more substituents        selected from halo, hydroxy and C₁₋₂ alkoxy,    -   R^(Y), R^(Y1) and/or R^(Y2) independently represent C₁₋₆ alkyl,        C₃₋₇ cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six        groups are substituted by hydroxy and are optionally further        substituted by one or more substituents selected from C₁₋₂        alkyl, halo, hydroxy, C₁₋₂ alkoxy, C(O)OH, C(O)O—(C₁₋₄ alkyl)        and —N(R^(a))(R^(b)), and which Het² group is optionally further        substituted with one or more oxo groups,    -   R^(1D) represents C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇        cycloalkyl, phenyl, Het¹ or Het², which latter seven groups are        substituted by hydroxy and are optionally further substituted by        one or more substituents selected from C₁₋₂ alkyl, halo, cyano,        hydroxy and C₁₋₂ alkoxy;    -   R⁴ represents —CH₂OH,    -   R^(6b) represents C₁₋₈ alkyl, C₃₋₈ cycloalkyl, phenyl, Het¹ or        Het², which latter five groups are substituted by hydroxy and        are optionally further substituted by one or more substituents        selected from halo, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, —C₁₋₃        alkylene-R^(6e) and CO₂H,    -   R^(6e) represents hydroxy or    -   R^(7a) represents H,        with a di-tert-butyl or dibenzyl di(C₁₋₄ alkyl)phosphoramidite        (e.g. di-tert-butyl diethylphosphoramidite (Dunn, D., et al., J.        Biol. Chem. 1996, 271, 168-173) or        dibenzyl-N,N-diisopropylphosphoramidite (Locher, C. P., et al.,        WO 2014/014845, 23 Jan. 2014)), under conditions known to those        skilled in the art, for example in the presence of an activator        (e.g. tetrazole or 5-methyl-1H-tetrazole) and an aprotic organic        solvent (e.g. THF or DMF), followed by reaction with an oxidant        (e.g. hydrogen peroxide or mCPBA) and then removal of the        tert-butyl or benzyl protecting groups (e.g. for the tert-butyl        protecting groups, by acid-catalysed hydrolysis, such as by        reaction with trifluoroacetic acid or, for the benzyl protecting        groups, by hydrogenation in the presence of a suitable catalyst        (e.g. a palladium catalyst, such as Pd/C), optionally in the        presence of a base (e.g. sodium hydroxide, sodium bicarbonate or        sodium carbonate));        (j) deprotection of an protected derivative of a compound of        formula I, under conditions known to those skilled in the art,        wherein the protected derivative bears a protecting group on an        O- or N-atom of the compound of formula I (and, for the        avoidance of doubt, a protected derivative of one compound of        formula I may or may not represent another compound of formula        I).

Examples of protected derivatives of compounds of formula I includethose where:

-   -   an O-atom is protected with a benzyl group, which benzyl group        may be removed by hydrogenation, for example in the presence of        a palladium catalyst (such as Pd/C);    -   an O-atom of an acid (e.g. a carboxylic, sulfonic, phosphonic or        phosphinic acid) is protected with an alkyl group (such as        methyl, ethyl or tert-butyl), which alkyl group may be removed        by either basic hydrolysis (e.g. for methyl or ethyl groups, by        a hydrolysis reaction using an alkali metal hydroxide such as        sodium hydroxide) or acid hydrolysis (e.g. for a tert-butyl        group, by a hydrolysis reaction using an acid such as        trifluoroacetic acid);    -   an N-atom of an amine is protected with a carbamate group, such        as a benzyl or tert-butyl carbamate, which groups may be removed        under similar conditions to those used to remove benzyl or        tert-butyl groups from O-atoms.

Protected derivatives of compounds of formula I in which R⁴ represents—[C₁₋₄ alkylene]₀₋₁—CO₂H also include compounds of formula VIIa, ashereinbefore defined, in which Q^(x) represents —[C₁₋₄alkylene]₀₋₁-C(O)OR^(4′) (e.g. Q^(x) represents —C(O)OR^(4′)) and R^(4′)represents a C₁₋₄ alkyl group (e.g. a C₄ alkyl group or a C₁₋₃ alkylgroup, such as methyl).

Thus, the process described at (j) above encompasses, for example, aprocess for the preparation of a compound of formula I in which R⁴represents -Q⁴-P(O)(OR⁹)(R⁷) and R⁹ represents H, which processcomprises hydrolysing a corresponding compound of formula I in which R⁴represents -Q⁴-P(O)(OR⁹)(R⁷) and R⁹ represents C₁₋₄ alkyl, which lattergroup is optionally substituted by one or more halo atoms or by phenyl,which phenyl group is optionally substituted by one or more substituentsselected from halo, OH, C₁₋₃ alkyl and C₁₋₃ alkoxy (e.g. a correspondingcompound of formula I in which R⁴ represents -Q⁴-P(O)(OR⁹)(R⁷) and R⁹represents methyl or ethyl). The hydrolysis may be basic hydrolysis(e.g. for methyl or ethyl groups, by a hydrolysis reaction using analkali metal hydroxide such as sodium hydroxide), for example conductedat elevated temperature (such as from 30 to 70° C. or, particularly,from 40 to 50° C.) in the presence of an aqueous solvent mixture (e.g. asolvent comprising water and one or more polar organic solvents such asone or more water-miscible, polar organic solvents (e.g. an aproticsolvent such as dioxane and/or a protic solvent such as ethanol)).

Compounds of formula II may be prepared according to or by analogy withmethods known to those skilled in the art, for example by reaction of acompound of formula IIa, as defined above, with an azide-forming agent,followed by rearrangement of the intermediate acyl azide (as describedat (b) above; see, for example, Tetrahedron 1974, 30, 2151-2157).

Compounds of formula IIb may be prepared reaction of a compound offormula VIII,

wherein LG¹ is as hereinbefore defined, with a compound of formula IX,

wherein Z¹ is as hereinbefore defined, for example under conditionsknown to those skilled in the art.

Amines of formula IX may be prepared from carboxylic acids of formulaIIa through the route described in (b) above, where the intermediateisocyanate II is hydrolysed with water to give a carbamic acid thatloses carbon dioxide to furnish IX. By the same token, the intermediateisocyanate II can be reacted with an alcohol, such as t-butanol, togenerate a protected version of IX.

Certain compounds of formula III in which Z² represents a structuralfragment of formula V, or compounds of formula IX in which Z¹ representsa structural fragment of formula V, may be synthesised employing theroute outlined in Scheme 1 (see, for example: WO 2003/072569; and WO2008/046216), wherein R² to R⁴, R^(5a) and X¹ to X³ are as hereinbeforedefined (e.g. X³ represents CR^(5b) and R² to R⁴, R^(5a), R^(5b), X¹ andX² are as hereinbefore defined), LG³ and LG⁴ represent leaving groups,e.g. halogen or methanesulfonyl, and FG represents a real or latent NH₂group, i.e., a group that is readily transformed into an NH₂ group, suchas nitro or a protected variant NH-PG², where PG² is a typicalprotecting group (see, for example: Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis; Wiley, 4th revised edition,2006; ISBN-10: 0471697540), e.g. a carbamate ester or carboxamide. Thesequence starts with the base-mediated S_(N)Ar displacement of LG³ in XIby the aroxides formed when X is treated with base to generate ethersXII. The remaining halogen or methanesulfonyl substituent (LG⁴) of theether XII is then displaced (i) by an amine of formula VII in a secondS_(N)Ar reaction or (ii) via a Buchwald coupling (see, for example, WO2009/017838) with an amine of formula VII to furnish the desiredcompound (when FG is NH₂), or XIII (when FG is nitro or NH-PG²). When FGis nitro in XIII, the NH₂ group may be revealed by a reduction reaction,typically done through hydrogenation employing a suitable catalyst, e.g.palladium on carbon, or employing dissolving metal conditions, such aswith iron in glacial acetic acid. Alternatively, when FG is a protectinggroup, the NH₂ group may be revealed by a deprotection reaction.Although only depicted as taking place in the final step of thesequence, it should be noted that the unmasking of the latent NH₂ grouprepresented by FG can take place at any stage in the synthetic routeshown in Scheme 1.

In a similar manner, amines of formula IX in which Z¹ represents astructural fragment of formula IV may be synthesised by conversion of alatent to a real NH₂ group in a compound of formula XIIIa,

wherein FG′ is as defined for FG above, except that it does notrepresent NH₂, and R^(1A) to R^(1E) are as hereinbefore defined.

Compounds of formula III in which Z² represents a structural fragment offormula V, or compounds of formula IX in which Z¹ represents astructural fragment of formula V, wherein, in the structural fragment offormula V, R⁴ represents

-   -   -Q^(1a)-NR⁸—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—O]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q^(2a)-NR⁸—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   -Q^(3a)-NR⁸—[C₁₋₄ alkylene]₀₋₁-Het³,        which C₁₋₅ alkylene and Het³ groups are optionally substituted        as described above, may be prepared by analogy with processes        described herein for preparing compounds of formula I (see        process (f) above) and other compounds of formula III (see, for        example, Scheme 1 above), for example by reaction of a compound        of XIIIb

wherein FG, R², R³, R^(5a), L, X¹ to X³ and Q^(x) are as hereinbeforedefined (e.g. X³ represents CR^(5b) and FG, R², R³, R^(5a), R^(5b), L,X¹, X² and Q^(x) are as hereinbefore defined), with a compound offormula VIIb, VIIc or VIId, as hereinbefore defined, under conditionsknown to those skilled in the art (for example the peptide couplingconditions described in respect of process (f) above), followed byconversion (if necessary) of FG to NH₂, for example as described abovein connection with Scheme 1.

Compounds of formula VI may be synthesised by analogy with the compoundsof formula I (see, for example, alternative processes (a) to (c) above).For example, compounds of formula VI can be prepared by reaction of acompound of formula IIx with a compound of formula IIIx, wherein thecompounds of formulae IIx and IIIx take the same definitions as thecompounds of formulae II and III, with the exception that one of Z¹ andZ² represents a structural fragment of formula IV, as hereinbeforedefined, and the other of Z¹ and Z² represents a structural fragment offormula Va,

Compounds of formula VII in which L represents a direct bond may beprepared according to or by analogy with procedures known to thoseskilled in the art, for example as described below.

-   (i) For compounds of formula VII in which R⁴ represents    -   —O—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)        or    -   —O—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a),    -   which C₁₋₅ alkylene groups is optionally substituted as        described above, reaction of a compound of formula XIV,

-    wherein FG¹ either represents FG or C(O)O—(C₁₋₆ alkyl), and FG,    R^(5a), X² and X³ are as hereinbefore defined (e.g. X³ represents    CR^(5b) and FG, R^(5a), R^(5b) and X² are as hereinbefore defined),    with a compound of formula XVa or XVb

LG⁵-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a1)  XVa

LG⁵-C(R^(6c))(R^(6d))—[C₁₋₅alkylene]-R^(6a1)  XVb

-    which C₁₋₅ alkylene groups is optionally substituted as described    above, wherein LG⁵ represents a suitable leaving group such as halo,    (perfluoro)alkane-sulfonate or arylsulfonate (e.g. methanesulfonate    or p-toluenesulfonate) and R^(6a1), R^(6c) and R^(6d) are as    hereinbefore defined, under conditions known to those skilled in the    art (e.g. in the presence of an organic solvent and either a    suitable base, followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above)        and/or by deprotection of R^(6a1) when that group represents        C(O)O—C₁₋₄ alkyl.-   (ii) For compounds of formula VII in which R⁴ represents    -   —O—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)        or    -   —O—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a)-    which C₁₋₅ alkylene groups is optionally substituted as described    above, reaction of a compound of formula XIV, as hereinbefore    defined, with a compound of formula XVIa or XVIb

HO—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)  XVIa

HO—C(R^(6c))(R^(6d))—[C₁₋₅alkylene]-NR^(6a)  XVIb

-    which C₁₋₅ alkylene groups is optionally substituted as described    above, wherein R^(6a1), R^(6c) and R^(6d) are as hereinbefore    defined, under conditions known to those skilled in the art (e.g.    under Mitsunobu conditions, i.e. in the presence of using    triphenylphosphine and an azodicarboxylate, such as diethyl    azodicarboxylate or diisopropyl azodicarboxylate), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above)        and/or by deprotection of R^(6a1) when that group represents        C(O)O—C₁₋₄ alkyl.-   (iii) For compounds of formula VII in which R⁴ represents    -   —S—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   —S—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   —S—R^(6b),-    which C₁₋₅ alkylene groups is optionally substituted as described    above, reaction of a compound of formula XVII,

-    wherein FG¹, R^(5a), X² and X³ are as hereinbefore defined (e.g. X³    represents CR^(5b) and FG¹, R^(5a), R^(5b) and X² are as    hereinbefore defined), with a compound of formula XVa or XVb, as    hereinbefore defined, or a compound of formula XVIII

LG⁵-R^(6b)  XVIII

-    wherein LG⁵ and R^(6b) are as hereinbefore defined, under    conditions known to those skilled in the art (e.g. in the presence    of a suitable base and an organic solvent), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (iv) For compounds of formula VII in which X² represents CR^(Z) and    R⁴ represents    -   —S(O)₁₋₂—[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   —S(O)₁₋₂—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   —S(O)₁₋₂-R^(6b),-    which C₁₋₅ alkylene groups is optionally substituted as described    above, oxidation of a compound of formula XIX,

-    wherein R represents    -   —[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁ CH₂—R^(6a),    -   —C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   —R^(6b),-    which C₁₋₅ alkylene groups is optionally substituted as described    above, and wherein FG¹, R^(5a), X³ and R^(Z) are as hereinbefore    defined (e.g. X³ represents CR^(5b) and FG¹, R^(5a), R^(5b) and    R^(Z) are as hereinbefore defined), under conditions known to those    skilled in the art (e.g. in the presence of a peracid, such as    meta-chloroperbenzoic acid), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (v) For compounds of formula VII in which R⁴ represents —S—R^(6b),    coupling of a compound of formula XX

-    wherein LG⁶ represents a suitable leaving group such as halo or    trifluoromethanesulfonate, FG¹, R^(5a), X² and X³ are as    hereinbefore defined (e.g. X³ represents CR^(5b) and FG¹, R^(5a),    R^(5b) and X² are as hereinbefore defined), with a compound of    formula XXI,

H—S—R^(6b)  XXI

-    wherein R^(6b) is as hereinbefore defined, under conditions known    to those skilled in the art (e.g. in the presence of a Pd(0)    catalyst, Cu(I) iodide and a suitable base), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (vi) For compounds of formula VII in which R⁴ represents    -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—O]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a)-    wherein Q¹ and R^(6a) are as hereinbefore defined, reaction of a    compound of formula XXII

-    in which R^(4a) represents    -   -Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—O]_(x)—CH₂(CH₂)₀₋₁CH₂—OH-    and R^(5a), X² and X³ are as hereinbefore defined (e.g. X³    represents CR^(5b) and R^(5a), R^(5b) and X² are as hereinbefore    defined),-    with a compound of formula XXIII,

LG⁵-[CH₂(CH₂)₀₋₁CH₂—O]_(y)—CH₂(CH₂)₀₋₁CH₂—R^(6a)  XXIII

-    wherein x and y are integers from 0 to 11, the sum of x and y being    from 0 to 11, and Q¹, LG⁵ and R^(6a) are as hereinbefore defined,    under conditions known to those skilled in the art (e.g. at ambient    temperature in the presence of a base such as sodium hydride and a    polar organic solvent such as DMF).-   (vii) For compounds of formula VII in which X² represents CR^(Z) and    R⁴ represents    -   —S—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-N(R^(7b))R^(7c)-    which C₁₋₅ alkylene groups is optionally substituted as described    above, reaction of a compound of formula XXIV,

-    wherein R′ represents    -   —C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-LG⁶-    which C₁₋₅ alkylene groups is optionally substituted as described    above, with a compound of formula HN(R^(7b))R^(7c), wherein FG¹,    R^(5a), R^(6c), R^(6d), R^(7b), R^(7c), R^(Z), X³ and LG⁶ are as    hereinbefore defined (e.g. X³ represents CR^(5b) and FG¹, R^(5a),    R^(5b), R^(6c), R^(6d), R^(7b), R^(7c), R^(Z) and LG⁶ are as    hereinbefore defined), under conditions known to those skilled in    the art (for example in the presence of a suitable organic solvent    (e.g. acetone) and, optionally, catalyst for nucleophilic    displacement, such as an iodide sale (e.g. sodium iodide)), followed    by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (viii) For compounds of formula VII in which R⁴ represents    -   -Q^(1a)-NR⁸—[CH₂(CH₂)₀₋₁CH₂—O]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),    -   -Q^(2a)-NR⁸—C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a) or    -   -Q^(3a)-NR⁸—[C₁₋₄ alkylene]₀₋₁-Het³,-    which C₁₋₅ alkylene group is optionally substituted as described    above, reaction of a compound of formula XXV,

-    wherein FG¹, R^(5a), R^(6a), R^(6c), R^(6d), X², X³ and Q^(x) are    as hereinbefore defined (e.g. X³ represents CR^(5b) and FG¹, R^(5a),    R^(5b), R^(6a), R^(6c), R^(6d), X² and Q^(x) are as hereinbefore    defined), with a compound of formula VIIb, VIIc or VIId, as    hereinbefore defined, under conditions known to those skilled in the    art (for example the peptide coupling conditions described in    respect of process (f) above), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (ix) For compounds of formula VII in which R⁴ represents    —S(O)₂—R^(6b), coupling of a compound of formula XX, as hereinbefore    defined, with a compound of formula XXVI,

(M^(s+))(⁻O—S(O)—R^(6b))_(s)  XXVI

-    wherein M^(s+) is a metal cation, s is 1 or 2 (e.g. s is 1 and M is    an alkali metal such as potassium or, particularly, sodium) and    R^(6b) is as hereinbefore defined, under conditions known to those    skilled in the art (e.g. at elevated temperature (e.g. 80 to 100°    C.) in the presence of: a suitable transition metal catalyst, such    as Cu(I) iodide; an aprotic organic solvent, such as DMSO; a    suitable base, such as an alkali metal hydroxide (e.g. NaOH); and,    optionally, an organic ligand for Cu(I), such as L-proline),    followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (x) For compounds of formula VII in which R⁴ represents    —P(O)(OR⁹)(R⁷), reaction of a compound of formula XX, as    hereinbefore defined, with a compound of formula XXVIa,

HP(O)(OR⁹⁹)(R⁷)  XXVIa

-    wherein R⁹⁹ represents a C₁₋₄ alkyl group optionally substituted by    one or more halo atoms or phenyl (e.g. R⁹⁹ represents ethyl), and R⁷    is as hereinbefore defined, under conditions known to those skilled    in the art (e.g. at elevated temperature (e.g. 80 to 100° C.) in the    presence of a suitable catalyst (such as Xantphos G3 palladacycle    precatalyst (i.e.    [(4,5-bis(diphenylphosphino)-9,9-dimethyxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate) or Pd(Ph₃P)₄), a base (e.g. diisopropylethylamine    or triethylamine) and an aprotic organic solvent, such as toluene,    followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (xa) For compounds of formula VII in which R⁴ represents    —CH₂—P(O)(OR⁹)(R⁷), reaction of a compound of formula XXa

-    wherein LG⁶ is as hereinbefore defined (e.g. bromo) and R^(5a), X²,    X³ and FG¹ are as hereinbefore defined (e.g. X³ represents CR^(5b)    and R^(5a), R^(5b), X², FG¹ and LG⁶ are as hereinbefore defined),    with a compound of formula XXVIaa,

P(R⁷)(OR⁹⁹)₂  XXVIaa

-    wherein R⁷ and R⁹⁹ are as hereinbefore defined, followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).-   (xb) For compounds of formula VII in which R⁴ represents —[C₀₋₃    alkylene]-CH₂C(O)OR^(4′), coupling of a compound of formula XXb

-    wherein LG⁶ represents a suitable leaving group such as halo or    trifluoromethanesulfonate, FG^(1′) represents NH-PG² or NO₂, and    R^(5a), X² and X³ are as hereinbefore defined (e.g. X³ represents    CR^(5b) and R^(5a), R^(5b) and X² are as hereinbefore defined), with    a malonate ester of formula XXc

CH₂(CO₂R^(4′))₂  XXc

-    for example under conditions known to those skilled in the art    (e.g. in the presence of Cu(I) bromide and a suitable base, e.g.,    sodium hydride), followed by hydrolysis, decarboxylation and    re-esterification with R^(4′)OH, then    -   when FG¹ represents NH-PG², removal of the PG² protecting group        or    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂.-   (xi) For compounds of formula VII in which R⁴ represents Het^(x2)    and Het^(x2) is an N-linked heterocyclic group that is optionally    substituted as described above, reaction of a compound of formula    XX, as hereinbefore defined, in which FG¹ represents NO₂, with a    compound of formula XXVIb,

Het^(x3)-H  XXVIb

-    wherein Het^(x3) is a heterocycle as defined for Het^(x2) above,    which heterocycle contains an N-atom that (at least in one    tautomeric form) is linked to the hydrogen atom depicted, for    example in the presence of a base (e.g. Cs₂CO₃) followed by    reduction of NO₂ (FG¹) to NH₂.-   (xii) For compounds of formula VII in which R⁴ represents    tetrazol-5-yl, reaction of a compound of formula XXVIc,

-    wherein R^(5a), X², X³ and FG¹ are as hereinbefore defined (e.g. X³    represents CR^(5b) and R^(5a), R^(5b), X² and FG¹ are as    hereinbefore defined), with azidotributylstannane, for example at    elevated temperature in the presence of a polar, aprotic organic    solvent (e.g. dimethoxyethane), followed by    -   when FG¹ represents NH-PG², removal of the PG² protecting group,    -   when FG¹ represents NO₂, reduction of NO₂ to NH₂ or    -   when FG¹ represents C(O)O—(C₁₋₆ alkyl), saponification to        provide the corresponding carboxylic acid and then reaction with        a suitable azide-forming agent and thermal rearrangement of the        resulting acyl azide (see, for example, process (b) above).

Compounds of formula VII in which L represents C₁₋₂ alkylene may beprepared by analogous procedures.

Compounds of formula VIIa in which in which Q^(x) represents —[C₁₋₄alkylene]₀₋₁—C(O)OR^(4′) and R^(4′) represents a C₁₋₄ alkyl group (e.g.a C₄ alkyl group or a C₁₋₃ alkyl group, such as methyl) may be preparedby analogy with the procedures described herein for preparation ofcompounds of formula I (see, for example, processes (a) to (d) andScheme 1 above), or of formula Ib in which R^(1A) and R^(5a) bothrepresent methoxy, R^(1B) represents —NHS(O)₂CH₃, R^(1D) representstert-butyl, X¹ and X² both represent CH, R^(5b) represents H and R⁴represents —CO₂H.

For example, R⁴ may be replaced by —[C₁₋₄ alkylene]₀₋₁-C(O)OR^(4′) (e.g.—C(O)OR^(4′)) in:

-   -   the structural fragment of formula V (to give a structural        fragment of formula Vp, and corresponding compounds of formulae        IIp, IIap, IIbp and IIIp, in which Z¹ and Z² are replaced by        Z^(1p) and Z^(2p), respectively, wherein one of Z^(1′) and        Z^(2p) is a structural fragment of formula IV, as defined above,        and the other of Z^(1′) and Z^(2p) is a structural fragment of        formula Vp); or    -   the compound of formula VII (to give a compound of formula        VIIp).

Alternatively, compounds of formula VIIa in which Q^(x) represents—[C₁₋₄ alkylene]₀₋₁-C(O)OR^(4′) (e.g. —C(O)OR^(4′)) and R^(4′)represents a C₁₋₄ alkyl group (e.g. a C₄ alkyl group or a C₁₋₃ alkylgroup, such as methyl) may be prepared by converting, in a compound offormula XIIIb

the group FG to NH₂, wherein Q^(x) represents —[C₁₋₄alkylene]₀₋₁-C(O)OR^(4′) (e.g. —C(O)OR^(4′)) and R^(4′) represents aC₁₋₄ alkyl group (e.g. a C₄ alkyl group or a C₁₋₃ alkyl group, such asmethyl) and FG is as hereinbefore defined (e.g. by converting FG to NH₂as described above in connection with Scheme 1), followed by reactionwith, for example, a compound of formula IIb where Z¹ represents astructural fragment of formula IV.

Compounds of formula VIIb and VIIc in which R^(6a1) represents OR^(7a)in which R^(7a) represents P(O)(OH)₂ (or a di-O-tert-butyl ordi-O-benzyl protected derivative thereof) may be prepared by reaction ofa corresponding compound of formula VIIb and VIIc, in which R^(6a1)represents OR^(7a) where R^(7a) represents H, with di-tert-butyldiethylphosphoramidite or dibenzyl-N,N-diisopropylphosphoramidite, forexample in the presence of an activator (e.g. tetrazole or5-methyl-1H-tetrazole) and an aprotic organic solvent (e.g. THF or DMF),followed by reaction with an oxidant (e.g. hydrogen peroxide or mCPBA)and then optionally followed by removal of the tert-butyl or benzylprotecting groups by hydrolysis using an acid (such as trifluoroaceticacid) or by hydrogenation in the presence of a suitable catalyst (e.g. apalladium catalyst, such as Pd/C), respectively, which deprotection stepcan alternatively be performed upon a compound formed using a compoundof formula VIIb or VIIc (e.g. a compound of formula I).

Similar interconversions of functional groups may also be employed toprepare compounds of formula XIIIa. For example, compounds of formulaXIIIa in which R^(1B) represents —CH₂CN may be prepared by reaction of acompound of formula XXVII,

wherein FG, LG², R^(1A) and R^(1C) to R^(1E) are as hereinbeforedefined, with a source of cyanide ion (e.g. NaCN), for example underconditions known to those skilled in the art, such as in the presence ofa polar, aprotic organic solvent (e.g. DMSO).

Also, compounds of formula XIIIa in which R^(1B) represents—NR^(X)S(O)₂R^(Y1) in which R^(X) represents —CH₂—C₁₋₅ alkyl optionallysubstituted by one hydroxy (or a O-protected derivative thereof) may beprepared by reaction of a compound of formula XIIIa in which R^(1B)represents —N(H)S(O)₂R^(Y1) with a compound of formula XXVIIa,

LG²-CH₂—C₁₋₅alkyl-O-PG  XXVIIa

wherein PG represents a protecting group such as benzyl and LG² is ashereinbefore defined, for example in the presence of a base (e.g. K₂CO₃)and a polar organic solvent (e.g. DMF), optionally followed by removalof the PG protecting group (e.g. in the case of benzyl, by hydrogenationin the presence of a palladium catalyst), which deprotection step canalternatively be performed upon a compound formed using the compound offormula XIIIa (e.g. a compound of formula I or IIb).

Compounds of formula XXIV in which LG⁶ represents halo can be preparedaccording to or by analogy with procedures known to those skilled in theart, for example by reaction of a compound of formula XXVIII,

wherein R″ represents —CH₂—[C₁₋₅ alkylene]-OH, with a halogenating agent(e.g. a mixture of 2,4,6-trichloro,1,3,5-triazine anddimethylformamide).

Compounds of formula XXVII may be prepared according to (or by analogywith) procedures know to those skilled in the art. For example,compounds of formula XXVII in which LG² represents Cl may be prepared bychlorination of a corresponding compound of formula XXIX,

wherein FG, R^(1A) and R^(1C) to R^(1E) are as hereinbefore defined, forexample under conditions known to those skilled in the art, such as byreaction with thionyl chloride.

Compounds of formula XXIX may, for example, be prepared by reduction ofcorresponding compounds of formula XXX,

wherein FG, R^(X), R^(1A) and R^(1C) to R^(1E) are as hereinbeforedefined, for example under conditions known to those skilled in the art,such as by reaction with borohydride or aluminium hydride-based reducingagent (e.g. an alkali metal borohydride or aluminium hydride, such aslithium borohydride or lithium aluminium hydride) in the presence of areaction-inert organic solvent.

It will be understood by persons skilled in the art that compoundsrepresented by formulae II, IIx and IIb are generally reactiveintermediates. These intermediates may be formed in situ and reacteddirectly, without isolation, with compounds of formula III to providecompounds of formula I. Furthermore, it will be understood by thoseskilled in the art that the use of appropriate protective groups may berequired during the processes described above for any of the groups Z¹and Z² which possess chemically-sensitive functional groups, forexample, a hydroxyl group or an amino function.

Many of the compounds illustrated in the Schemes are either commerciallyavailable, or can be obtained using the cited procedures, or can bereadily prepared by conventional methods by those skilled in the art.See for example Regan, J. et al.; J. Med. Chem. 2003, 46, 4676-4686, WO2000/043384, WO 2007/053346, WO 2007/087448, WO 2007/089512, WO2009/117080 and WO 2014/027209.

Novel intermediates as described herein form an aspect of the invention.In this respect, further aspects of the invention relate to:

-   (i) a compound of formula II, IIa or IIb as hereinbefore defined,    wherein Z¹ represents a structural fragment of formula V, or a salt    or protected derivative thereof;-   (ii) a compound of formula III as hereinbefore defined, wherein Z²    represents a structural fragment of formula V, or a salt or    protected derivative thereof;-   (iii) a compound of formula VII as hereinbefore defined, wherein R⁴    represents -Q⁴-P(O)(OR⁹)(R⁷), or a salt or protected derivative    thereof;-   (iv) a compound of formula VIIa as hereinbefore defined (e.g. a    compound of formula VIIa in which Q^(x) represents —[C₁₋₄    alkylene]₀₋₁-C(O)O—C₁₋₄ alkyl (e.g. —C(O)O—C₄ alkyl or,    particularly, —C(O)O—C₁₋₃ alkyl) or —S(O)₂-LG²), or a salt or    protected derivative thereof; and-   (v) a compound of formula XIII or XIIIb as hereinbefore defined, or    a salt or protected derivative thereof.

In these aspects of the invention, embodiments of the compounds offormulae II, IIa, IIb, III, VII, VIIa, XIII and XIIIb that may bementioned include those in which one or more (e.g. all) of the followingapply:

-   (a) X¹ represents N or, particularly, CH;-   (b) X² represents N or, particularly, CH;-   (c) X³ represents CR^(5b);-   (d) L represents a direct bond;-   (e) one of R^(5a) and R^(5b) (e.g. R^(5b)) represents H, halo (e.g.    chloro), methyl, ethyl, —N(CH₃)₂, hydroxy, difluoromethoxy,    trifluoromethoxy or, particularly, methoxy and the other of R^(5a)    and R^(5b) (e.g. R^(5a)) represents methyl, methoxy or,    particularly, H.

Other embodiments of the compounds of formulae II, IIa, IIb, III, VIIand XIII that may be mentioned include those in which one or more (e.g.all) of (a) to (e) above apply and/or:

-   (f) R⁴ represents —P(O)(OH)(CH₃) or —P(O)(OCH₂CH₃)(CH₃) or, for    compounds of formulae II, IIa, IIb, III and XIII only, R⁴ represents    —CO₂H.

Other embodiments of the compounds of formulae II, IIa, IIb, III, VIIa,XIII and XIIIb that may be mentioned include those in which one or more(e.g. all) of (a) to (f) above apply and/or:

-   (g) R² and R³, together with the C-atoms to which they are attached,    form a fused phenyl ring.

Particular compounds of formulae II, IIa, IIb, III, VIIa, XIII andXIIIb, or salts or protected derivatives thereof, that may be mentionedinclude those in which one or more (e.g. all) of the following apply:

R² and R³, together with the C-atoms to which they are attached, form afused phenyl ring;X¹, X² and X³ all represent CH;L represents a direct bond;R^(5a) represents methoxy; andR⁴ represents —CO₂H, or a protected form thereof.

Protected derivatives of the compounds of formulae III, VII, XIII andXIIIb include those in which the essential NH₂ group (or NH₂ grouprepresented by FG) is protected. In this respect, such protectedderivatives include amides or, particularly, carbamates of thosecompounds. For example, those protected derivatives include compounds inwhich a H-atom of the NH₂ group is replaced by:

-   -   R′—C(O)—, wherein R′ is H, C₁₋₈ alkyl, phenyl or benzyl, which        latter two groups are optionally substituted by one or more        groups selected from halo, hydroxy, methyl and methoxy; or    -   R″—O—C(O)—, wherein R″ is tert-butyl, phenyl, benzyl or        fluorenyl, which latter three groups are optionally substituted        by one or more groups selected from halo, hydroxy, methyl and        methoxy.

Protected derivatives of the compounds of formulae II, IIa, IIb, III,VII and XIII in which R⁴ represents —CO₂H additionally (oralternatively) include those in which the carboxyl moiety is protected.In this respect, such protected derivatives also include esters (e.g.C₁₋₈ alkyl esters, such as ethyl or, particularly, methyl esters) ofsuch compounds.

Those skilled in the art will appreciate that compounds of formula IIIin which Z² represents a structural fragment of formula V may beprotected at the essential NH₂ group and/or, when R⁴ represents —CO₂H,at the carboxyl moiety. In this respect, for example, particularprotected derivatives of compounds of formula III in which Z² representsa structural fragment of formula V that may be mentioned include:

-   methyl    4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate;-   methyl    4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate;    and-   tert-butyl    (4-((2-((4-(ethoxy(methyl)phosphoryl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate.

A particular compound of formula III that may be mentioned is ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate.

Alternative embodiments of the invention relate to a compound that iseither:

-   (i) a protected derivative of compound of formula III in which Z²    represents a structural fragment of formula V; or-   (ii) a compound of formula XIIIb, or a protected derivative thereof,    provided that said compound is not:-   methyl    4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate;    or-   methyl    4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate.

Still further embodiments of the invention relate to a compound offormula VIIa as hereinbefore defined, provided that said compoundeither:

(a) is; or(b) is not

-   methyl    4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate.

The aspects of the invention described herein (e.g. the above-mentionedcompounds, combinations, methods and uses) may have the advantage that,in the treatment of the conditions described herein, they may be moreconvenient for the physician and/or patient than, be more efficaciousthan, be less toxic than, have better selectivity over, have a broaderrange of activity than, be more potent than, produce fewer side effectsthan, have a better pharmacokinetic and/or pharmacodynamic profile than,have more suitable solid state morphology than, have better long termstability than, or may have other useful pharmacological propertiesover, similar compounds, combinations, methods (treatments) or usesknown in the prior art for use in the treatment of those conditions orotherwise.

The compounds of the invention may additionally (or alternatively):

-   -   exhibit a long duration of action and/or persistence of action        (e.g. in comparison to other previously disclosed p38 MAP kinase        inhibitors such as, for example, BIRB796);    -   exhibit potent inhibition of Syk (e.g. they may have an IC₅₀        against Syk of 500 nM or less, such as 350 nM or less);    -   not strongly inhibit GSK 3α (e.g. they may have an IC₅₀ against        GSK 3α of 1,000 nM or greater; such as 1,500, 2,000, 3,000,        4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or        greater);    -   target a smaller portion of the kinome, i.e., with improved        selectivity, as illustrated by lowered KinomeScan Selectivity        Scores;    -   maintain a relatively high local drug concentration between        doses (e.g. a high local concentration relative to other        previously disclosed p38 MAP kinase inhibitors such as, for        example, BIRB796);    -   exhibit properties that are particularly suited to topical/local        administration (e.g. following topical/local administration, the        generation of high target tissue concentrations but low plasma        concentrations of the compounds of formula (I) and/or rapid        clearance of the compounds of formula (I) from plasma, for        example as a result of high renal or hepatic extraction);    -   exhibit little or no β-catenin induction and/or inhibition of        mitosis in cells;    -   display reduced cytotoxicities;    -   not produce increases in binucleated cells containing        micronuclei in the human lymphocyte in vitro micronucleus test;    -   exhibit little or no time-dependent inhibition of members of the        cytochrome P450 superfamily;    -   show improved chemical stability in the presence of water (e.g.        stability to hydrolysis in aqueous mixtures at elevated        temperatures) compared to previously disclosed p38 MAP kinase        inhibitors such as, for example, BIRB796;    -   following administration to a patient, give rise to metabolites        associated with little or no safety (e.g. toxicity) concerns;    -   display reduced ocular irritancy or toxicity in both preclinical        species and humans following topical administration;    -   exhibit good aqueous solubility and/or cellular permeability        (e.g. exhibit good aqueous solubility and potent inhibition of        the release of certain cytokines, such as IL-8 and/or IFNγ, in        cells);    -   be more readily formulated in aqueous solution in the pH range        7-8 with lower quantities of solubilising excipients;    -   have a high degree of crystallinity; and/or exhibit little or no        hygroscopicity in the solid state.

EXPERIMENTAL METHODS General Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated orunder a balloon of hydrogen. Microwave reactions were performed in a CEMDiscover and Smithcreator microwave reactor, heating to a constanttemperature using variable power microwave irradiation.

Normal phase column chromatography was routinely carried out on anautomated flash chromatography system such as CombiFlash Companion orCombiFlash RF system using pre-packed silica (230-400 mesh, 40-63 μm)cartridges. SCX was purchased from Supelco and treated with 1Mhydrochloric acid prior to use. Unless stated otherwise the reactionmixture to be purified was first diluted with MeOH and made acidic witha few drops of AcOH. This solution was loaded directly onto the SCX andwashed with MeOH. The desired material was then eluted by washing with1% NH₃ in MeOH.

Analytical Methods

Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μm, 4.6×30 mmcolumn eluting with a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. UV spectra of the eluted peaks were measured using either adiode array or variable wavelength detector on an Agilent 1100 system.

Analytical LCMS was carried out using a Waters Xselect CSH C18, 2.5 μm,4.6×30 mm column eluting with a gradient of 0.1% Formic Acid in MeCN in0.1% aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μm, 4.6×30 mmcolumn eluting with a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. UV and mass spectra of the eluted peaks were measured usinga variable wavelength detector on either an Agilent 1200 or an AgilentInfinity 1260 LCMS with 6120 single quadrupole mass spectrometer withpositive and negative ion electrospray.

Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 μm,19×50 mm column using either a gradient of either 0.1% Formic Acid inMeCN in 0.1% aqueous Formic Acid or a gradient of MeCN in aqueous 10 mMAmmonium Bicarbonate or employing a Waters Xbridge BEH 018, 5 μm, 19×50mm column using a gradient of MeCN in aqueous 10 mM AmmoniumBicarbonate. Fractions were collected following detection by UV at asingle wavelength measured by a variable wavelength detector on a Gilson215 preparative HPLC or Varian PrepStar preparative HPLC or by mass andUV at a single wavelength measured by a ZQ single quadrupole massspectrometer, with positive and negative ion electrospray, and a dualwavelength detector on a Waters FractionLynx LCMS.

¹H NMR Spectroscopy: ¹H NMR spectra were acquired on a Bruker Avance IIIspectrometer at 400 MHz. Either the central peaks of chloroform-d,dimethylsulfoxide-d₆ or an internal standard of tetramethylsilane wereused as references.

Preparation of Compounds of the Invention Example 14-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid

(i) tert-Butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamateMethod 1

A mixture of 4-((2-chloropyridin-4-yl)oxy)naphthalen-1-amine (see, forexample, Ito, K. et al., WO 2010/112936, 7 Oct. 2010; 1000 mg, 3.69mmol) and di-tert-butyl dicarbonate (750 mg, 3.44 mmol) in t-BuOH (10mL) was stirred at reflux for 18 h. The mixture was diluted with water(15 mL) and the solid collected by filtration. The solid was trituratedin diethyl ether to yield the sub-title compound (1002 mg) as a palegrey solid.

¹H NMR (DMSO-d6) 400 MHz, δ: 9.37 (s, 1H), 8.28 (d, 1H), 8.16 (d, 1H),8.82 (dd, 1H), 7.66 (d, 1H), 7.66-7.54 (m, 2H), 7.40 (d, 1H), 7.03 (d,1H), 6.91 (dd, 1H), 1.52 (s, 9H).

LCMS m/z 371 (M+H)⁺ (ES⁺); 369 (M−H)⁻ (ES⁻)

Method 2

2-Chloro-4-fluoropyridine (33 mL, 365 mmol) was added to a mixture oftert-butyl (4-hydroxynaphthalen-1-yl)carbamate (85 g, 328 mmol) andCs₂CO₃ (139 g, 426 mmol) in DMSO (600 mL) and stirred at rt for 24 h.Water (1 L) was added, the mixture stirred for 1 h, then the precipitatefiltered off. The reaction was repeated on a further 85 g scale ofnaphthol. The combined precipitates were washed with water (2 L), ether(4×400 mL) and dried under vacuum at 70° C. for 72 h to afford thesub-title compound (201.6 g) as a light grey solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.28 (d, 1H), 8.16 (d, 1H),7.82 (d, 1H), 7.67-7.56 (m, 3H), 7.40 (d, 1H), 7.03 (d, 1H), 6.92 (dd,1H), 1.52 (s, 9H).

LCMS m/z 371 (M+H)⁺ (ES⁺); 369 (M−H)⁻ (ES⁻)

(ii) Methyl4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoateMethod 1

A suspension of the product from step (i) above (2.0 g, 5.39 mmol),methyl 4-amino-2-methoxybenzoate (1.0 g, 5.52 mmol), BINAP (300 mg,0.482 mmol) and cesium carbonate (3.5 g, 10.74 mmol) in 1,4-dioxane (30mL) was degassed with nitrogen for 10 min. Pd₂dba₃ (200 mg, 0.218 mmol)was added and the mixture was heated to 90° C. overnight. The mixturewas diluted with diethyl ether (60 mL) and filtered. The filtrate wasthen washed with water (2×100 mL), and saturated brine (50 mL). Theorganic phase was dried (MgSO₄), filtered and concentrated under reducedpressure to yield the crude product as a red foam. The crude product waspurified by chromatography on the Companion (80 g column, 20-50% EtOAcin hexane) to afford the sub-title compound (2.34 g) as a yellow foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 9.36 (s, 1H), 8.18 (d, 1H),8.14 (d, 1H), 7.83 (d, 1H), 7.54-7.66 (m, 5H), 7.37 (d, 1H), 7.22 (dd,1H), 6.69 (dd, 1H), 6.15 (d, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 1.53 (s,9H).

LCMS m/z 516 (M+H)⁺ (ES⁺)

Method 2

A mixture of methyl 4-amino-2-methoxybenzoate (10.8 g, 59.6 mmol), theproduct from step (i) above (20.09 g, 54.2 mmol) and potassium carbonate(15 g, 109 mmol) in DMF (300 mL) was degassed with N₂ for 10 min.BrettPhos G3 precatalyst (1 g, 1.103 mmol) was added and the mixtureheated at 85° C. for 3 h. The mixture was cooled then partitionedbetween DCM (500 mL) and water (800 mL). The organic layer was washedwith water (500 mL), dried (MgSO₄), filtered and evaporated underreduced pressure. The residue was triturated with ether, filtered anddried to afford the sub-title compound (21.7 g) as a grey solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.36 (s, 1H), 8.18 (d, 1H),8.14 (d, 1H), 7.83 (d, 1H), 7.54-7.66 (m, 5H), 7.38 (d, 1H), 7.22 (dd,1H), 6.69 (dd, 1H), 6.14 (d, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 1.53 (s,9H).

LCMS m/z 516 (M+H)⁺ (ES⁺)

(iii) Methyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate

TFA (7 mL, 91 mmol) was added to a solution of the product from step(ii) above (2.34 g, 4.08 mmol) in DCM (50 mL) and the reaction stirredfor 2 h. The solvents were evaporated and the residue partitionedbetween sat NaHCO₃ soln. (100 mL) and DCM (60 mL). The organics wereseparated, dried (MgSO₄), filtered and the solvent evaporated to affordthe sub-title compound (1.5 g) as a pale brown foam.

LCMS m/z 416 (M+H)⁺ (ES⁺)

(iv) Phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate

Phenyl chloroformate (0.750 mL, 5.98 mmol) was added to a stirredsolution of N-(3-amino-5-(tert-butyl)-2-methoxyphenyl)methanesulfonamide(see, for example, Cirillo, P. F. et al., WO 2002/083628, 24 Oct. 2002;1.5 g, 5.51 mmol) and NaHCO₃ (1.0 g, 11.90 mmol) in THF (15 mL) and DCM(15 mL) and the mixture was stirred for 2 h. The mixture was washed withwater (20 mL) and the organic layer separated, dried (MgSO₄), filteredand evaporated to a brown foam which was stirred in cyclohexane (20 mL)to afford the sub-title compound (2.05 g) as a colourless solid.

LCMS m/z 393 (M+H)⁺ (ES⁺); 391 (M−H)⁻ (ES⁻)

(v) Methyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoateMethod 1

Triethylamine (20 μL, 0.143 mmol) was added to a solution of the productfrom step (iv) above (300 mg, 0.764 mmol) and the product from step (ii)above (300 mg, 0.722 mmol) in iPrOAc (15 mL) at 65° C. (blocktemperature) and the mixture stirred overnight. The reaction was cooledto rt and concentrated in vacuo affording a pale brown foam. The foamwas slurried in Et₂O (10 mL) for 2 h and the resulting solid collectedby filtration, washing with further portions of Et₂O, affording thesub-title compound (433 mg) as a pale pink solid.

LCMS m/z 358 (M+2H)²⁺ (ES⁺)

Method 2

Triethylamine (600 μL, 4.30 mmol) was added to a solution of the productfrom step (iv) above (9.0 g, 22.93 mmol) and the product from step (iii)above (9.0 g, 21.66 mmol) in iPrOAc (300 mL) at 65° C. (blocktemperature) and the mixture stirred for 24 h. The reaction was cooledto room temperature and concentrated in vacuo affording a brown foam.The crude product was purified by chromatography on the Companion (330 gcolumn, 1-5% MeOH in DCM) to afford the sub-title compound (13.2 g) as apale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.35 (s, 1H), 916 (s, 1H),8.93 (s, 1H), 8.31 (d, 1H), 8.17-8.20 (m, 2H), 8.13 (d, 1H), 7.87 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 2H), 7.53 (d, 1H), 7.41 (d, 1H),7.24 (dd, 1H), 7.03 (d, 1H), 6.69 (dd, 1H), 6.17 (d, 1H), 3.81 (s, 3H),3.74 (s, 3H), 3.71 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 714 (M+H)⁺ (ES⁺)

(vi)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid Method 1

An aqueous solution of lithium hydroxide monohydrate (25 mg, 0.596 mmol)in water (3 mL) was added to a solution of the product from step (v)above (433 mg, 0.540 mmol) in THF (2 mL) and methanol (1 mL) and themixture was stirred at rt overnight. Lithium hydroxide monohydrate (25mg, 0.596 mmol) was added and stirring was continued for a further 3days. The mixture was concentrated under reduced pressure to remove THFand methanol then diluted with water (25 mL). A solution of citric acidmonohydrate (250 mg, 1.190 mmol) in water (5 mL) was added and theresulting precipitate was collected by filtration to yield the titlecompound (360 mg) as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H), 9.39 (s, 1H), 9.31 (s,1H), 9.14 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.18 (d,1H), 8.12 (d, 1H), 7.87 (d, 1H), 7.71 (ddd, 1H), 7.63 (d, 1H), 7.61(ddd, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 7.22 (dd, 1H), 7.02 (d, 1H), 6.68(dd, 1H), 6.16 (d, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.10 (s, 3H), 1.27(s, 9H). 90% purity

LCMS m/z 700 (M+H)⁺ (ES⁺)

Method 2

To a stirred solution of the product from step (v) above (33.4 g, 45.9mmol) in THF (300 mL) was added NaOH (6M aq.) (85.0 mL, 510 mmol). MeOH(60 mL) was added and stirring continued for 28 h. The reaction wasconcentrated in vacuo affording a yellow solid. The material wassuspended in water (200 mL) and acidified with 6M HCl (100 mL) causing awhite solid to precipitate. The solid was collected by filtration,washing with water. The resulting solid was dried on the frit for 1 hthen further dried at 40° C. under vacuum affording the title compoundas the hydrochloride salt as a white solid.

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 9.59(s, 1H), 9.15 (s, 1H), 9.02 (s, 1H), 8.37 (d, 1H), 8.13-8.18 (m, 3H),7.86 (d, 1H), 7.70-7.74 (m, 1H), 7.62-7.66 (m, 2H), 7.44 (d, 1H), 7.35(s, 1H), 7.10 (d, 1H), 7.03 (d, 1H), 6.78 (d, 1H), 6.26 (d, 1H), 3.81(s, 3H), 3.75 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 700 (M+H)⁺ (ES⁺)

The hydrochloride salt was loaded in 2.0 g batches, dissolved in THF,onto a pre-conditioned cartridge of SCX resin (20 g of resin,conditioned in MeCN). The resin was washed with MeCN then the productreleased in 1% NH₃ in MeOH. The NH₃ fractions were combined andconcentrated in vacuo, affording the title compound (30 g) as the freeacid as a pale pink solid.

¹H NMR (of free acid; 400 MHz, DMSO-d6) δ: 9.56 (s, 1H), 9.28 (s, 1H),9.00 (s, 1H), 8.34 (d, 1H), 8.16-8.17 (m, 2H), 8.11 (d, 1H), 7.86 (d,1H), 7.69-7.71 (m, 1H), 7.57-7.63 (m, 2H), 7.48 (d, 1H), 7.40 (d, 1H),7.21 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.81 (s, 3H),3.73 (s, 3H), 3.09 (s, 3H), 1.27 (s, 9H).

LCMS m/z 700 (M+H)⁺ (ES⁺)

The free acid (1.0 g, 1.386 mmol) was suspended in an aqueous solutionof NaOH (0.057 g, 1.414 mmol) in water (25 mL). MeOH (5 mL) was addedand the mixture stirred until homogeneity was achieved. The resultingsolution was diluted with MeOH (20 mL) and concentrated in vacuo,affording a pale grey solid. The material was suspended in MeCN (5 mL),to which water (0.5 mL) was added and the suspension stirred over theweekend. The suspension was filtered and the resulting solid washed withMeCN (2×3 mL) and dried under vacuum at 50° C., affording the titlecompound as the sodium salt (940 mg) as a white solid.

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.07 (s, 1H),9.02 (s, 1H), 8.35 (d, 1H), 8.08-8.13 (m, 2H), 8.02 (d, 1H), 7.85 (d,1H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 1H), 7.37-7.43 (m, 2H), 7.30 (s,1H), 7.11 (dd, 1H), 7.03 (d, 1H), 6.61 (dd, 1H), 6.12 (d, 1H), 3.80 (s,3H), 3.65 (s, 3H), 2.96 (s, 3H), 1.25 (s, 9H).

LCMS m/z 700 (M+H)⁺ (ES⁺)

Example 24-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-morpholinoethyl)benzamide

HATU (50 mg, 0.131 mmol) was added to a stirred solution of Example 1above (80 mg, 0.102 mmol), 2-morpholinoethanamine (30 mg, 0.230 mmol)and Hünig's Base (50 μL, 0.286 mmol) in DMF (2 mL) and stirred at rtovernight. The mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL). The organic phase was washed with saturated brine(10 mL), dried (MgSO₄) and filtered. The solvent was removed underreduced pressure and the crude product was purified by preparative HPLC(Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5μm, 19×50 mm column, 20-50% MeCN in Water) to afford a colourless foam.The foam was dissolved in ethyl acetate (10 mL) then washed withsaturated NaHCO₃ solution (10 mL), saturated brine (10 mL), dried(MgSO₄), filtered and evaporated under reduced pressure to afford thetitle compound (27 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.21 (t, 1H), 8.19 (d, 1H), 8.17 (d, 1H),8.12 (d, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.71 (ddd, 1H), 7.62 (ddd,1H), 7.58 (d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.65 (dd,1H), 6.16 (d, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.66-3.55 (m, 4H),3.43-3.33 (m, 2H), 3.10 (s, 3H), 2.46 (t, 2H), 2.46-2.36 (m, 4H), 1.27(s, 9H).

LCMS m/z 812 (M+H)⁺ (ES⁺)

Example 34-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid

(i) Phenyl (5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)carbamate

Phenyl chloroformate (1.0 mL, 7.97 mmol) was added to a stirred solutionof 3-amino-5-(tert-butyl)-2-methoxybenzamide (1.32 g, 5.94 mmol) andNaHCO₃ (1.5 g, 17.86 mmol) in THF (25 mL) and DCM (50 mL) and themixture stirred overnight. The reaction was diluted with DCM (30 mL) andwater (50 mL) and the organic phase dried via hydrophobic frit thenconcentrated in vacuo affording a waxy white solid. The solid wasslurried in cyclohexane (40 mL) for 3 h then isolated by filtration toafford the sub-title compound (1.9 g) as a fluffy, white solid.

LCMS m/z 343 (M+H)⁺ (ES⁺)

(ii) Methyl4-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate

Triethylamine (20 μL, 0.143 mmol) was added to a solution of the productfrom step (i) above (250 mg, 0.730 mmol) and methyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate(see Example 1(iii) above; 300 mg, 0.722 mmol) in iPrOAc (15 mL) at 65°C. (block temperature) and the mixture stirred overnight. The reactionwas cooled to rt causing a solid to precipitate. The solid was collectedby filtration to afford the sub-title compound (150 mg) as a dark pinksolid. The filtrate was concentrated in vacuo affording a yellow oil.The oil was slurried in Et₂O for 2 h after which time the resultingsolid was recovered by filtration washing with more Et₂O to afford a2^(nd) crop of the product (246 mg) as a pale pink solid.

LCMS m/z 333 (M+2H)²⁺ (ES⁺), 90% purity

(iii)4-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid

An aqueous solution of lithium hydroxide monohydrate (25 mg, 0.596 mmol)in water (3 mL) was added to a solution of the product from step (ii)above (396 mg, 0.537 mmol) in THF (2 mL) and methanol (1 mL) and themixture was stirred at rt overnight. Lithium hydroxide monohydrate (25mg, 0.596 mmol) was added and stirring was continued for a further 3days. The mixture was concentrated under reduced pressure to remove THFand methanol then diluted with water (25 mL). A solution of citric acid(250 mg, 1.190 mmol) in water (5 mL) was added and the resultingprecipitate was collected by filtration to afford the title compound(300 mg) as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ 11.93 (br s, 1H), 9.47 (s, 1H), 9.31 (s,1H), 8.92 (s, 1H), 8.46 (d, 1H), 8.31 (d, 1H), 8.18 (d, 1H), 8.11 (d,1H), 7.87 (d, 1H), 7.73-7.66 (m, 1H), 7.71 (ddd, 1H), 7.63 (d, 1H), 7.61(ddd, 1H), 7.56 (br s, 1H), 7.51 (d, 1H), 7.41 (dd, 1H), 7.22 (d, 1H),7.22 (dd, 1H), 6.67 (dd, 1H), 6.17 (d, 1H), 3.83 (s, 3H), 3.75 (s, 3H),1.29 (s, 9H).

LCMS m/z 650 (M+H)⁺ (ES⁺)

Example 44-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-morpholinoethyl)benzamide

HATU (50 mg, 0.131 mmol) was added to a stirred solution of Example 3above (80 mg, 0.123 mmol), 2-morpholinoethanamine (30 mg, 0.230 mmol)and Hünig's Base (50 μL, 0.286 mmol) in DMF (2 mL) and stirred at rtovernight. The mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL). The organic phase was washed with saturated brine(10 mL), dried (MgSO₄) and filtered. The solvent was removed underreduced pressure and the crude product was purified by preparative HPLC(Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5μm, 19×50 mm column, 20-50% MeCN in Water) to afford a colourless foam.The foam was dissolved in ethyl acetate (10 mL) then washed withsaturated NaHCO₃ solution (10 mL), saturated brine (10 mL), dried(MgSO₄), filtered and evaporated under reduced pressure to afford thetitle compound (14 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.27 (s, 1H), 8.93 (s, 1H),8.46 (d, 1H), 8.31 (t, 1H), 8.21 (t, 1H), 8.17 (d, 1H), 8.11 (d, 1H),7.87 (d, 1H), 7.77 (d, 1H), 7.74-7.67 (m, 2H), 7.62 (ddd, 1H), 7.60-7.53(m, 2H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.22 (d, 1H), 6.65 (dd, 1H), 6.16(d, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.65-3.56 (m, 4H), 3.46-3.35 (m,2H), 2.46 (t, 2H), 2.46-2.36 (m, 4H), 1.29 (s, 9H).

LCMS m/z 762 (M+H)⁺ (ES⁺)

Example 54-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide

HATU (50 mg, 0.131 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid (see Example 1 above; 80 mg, 0.102 mmol),2-(2-(2-methoxyethoxy)-ethoxy)ethanamine (30 mg, 0.184 mmol) and Hünig'sbase (50 μL, 0.286 mmol) in DMF (2 mL) and stirred at rt overnight. Themixture was diluted with water (10 mL) and extracted with ethyl acetate(10 mL). The organic phase was washed with saturated brine (10 mL),dried (MgSO₄) and filtered. The solvent was removed under reducedpressure and the crude product was purified by preparative HPLC (Gilson,Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50mm column, 20-50% MeCN in Water) to afford a colourless foam. The foamwas dissolved in ethyl acetate (10 mL) then washed with saturated NaHCO₃solution (10 mL), saturated brine (10 mL), dried (MgSO₄) and filtered.The solvent was removed under reduced pressure and the residue waspurified by chromatography on the Companion (4 g column, 2-5% MeOH/DCM)to afford the title compound (19 mg) as a cream solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H),8.10 (t, 1H), 7.87 (d, 1H), 7.76 (d, 1H), 7.71 (ddd, 1H), 7.62 (ddd,1H), 7.59 (d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.02 (d, 1H), 6.66 (dd,1H), 6.15 (d, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.58-3.43 (m, 8H),3.47-3.36 (m, 4H), 3.22 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 845 (M+H)⁺ (ES⁺); 843 (M−H)⁻ (ES⁻)

Example 64-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide

HATU (50 mg, 0.131 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid (see Example 3 above; 80 mg, 0.123 mmol),2-(2-(2-methoxyethoxy)ethoxy)ethanamine (30 mg, 0.184 mmol) and Hünig'sBase (50 μL, 0.286 mmol) in DMF (2 mL) and stirred at rt overnight. Themixture was diluted with water (10 mL) and extracted with ethyl acetate(10 mL). The organic phase was washed with saturated brine (10 mL),dried (MgSO₄) and filtered. The solvent was removed under reducedpressure and the crude product was purified by preparative HPLC (Gilson,Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50mm column, 20-50% MeCN in Water) to afford a colourless foam. The foamwas dissolved in ethyl acetate (10 mL) then washed with saturated NaHCO₃solution (10 mL), saturated brine (10 mL), dried (MgSO₄) and filtered.The solvent was removed under reduced pressure and the residue waspurified by chromatography on the Companion (4 g column, 2-5% MeOH/DCM)to afford the title compound (9 mg) as a cream solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.28 (s, 1H), 8.93 (s, 1H),8.46 (d, 1H), 8.31 (d, 1H), 8.17 (d, 1H), 8.11 (d, 1H), 8.10 (t, 1H),7.87 (d, 1H), 7.78-7.67 (m, 3H), 7.62 (ddd, 1H), 7.61-7.55 (m, 2H), 7.41(d, 1H), 7.23 (dd, 1H), 7.22 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.85(s, 3H), 3.83 (s, 3H), 3.57-3.48 (m, 8H), 3.47-3.37 (m, 4H), 3.22 (s,3H), 1.27 (s, 9H).

LCMS m/z 795 (M+H)⁺ (ES⁺); 793 (M−H)⁻ (ES⁻)

Example 74-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide

HATU (80 mg, 0.210 mmol) was added to a solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid (see Example 1 above; 100 mg, 0.143 mmol),4-(2-aminoethyl)thiomorpholine 1-oxide (30 mg, 0.185 mmol) and Hünig'sBase (75 μL, 0.429 mmol) in N,N-dimethylformamide (2 mL) and stirred atrt for 2 h. The mixture was diluted with water (10 mL) then theprecipitate was collected by filtration and washed with water (2×3 mL).The filter cake was purified by chromatography on silica gel (12 gcolumn, 2% MeOH:DCM to 10%) and then by preparative HPLC (Waters, Acidic(0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mmcolumn, 20-50% MeCN in Water) to afford the title compound (18 mg) as acolourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.24-8.07 (m, 4H), 7.87 (d, 1H), 7.76 (d,1H), 7.74-7.67 (m, 1H), 7.66-7.59 (m, 1H), 7.57 (d, 1H), 7.40 (d, 1H),7.23 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.86 (s, 3H),3.81 (s, 3H), 3.46-3.35 (m, 2H), 3.10 (s, 3H), 3.01-2.81 (m, 4H),2.81-2.63 (m, 4H), 2.55 (t, 2H), 1.27 (s, 9H).

LCMS m/z 845 (M+H)⁺ (ES⁺)

Example 8N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

(i)N-(5-(tert-Butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

4-((2-Chloropyridin-4-yl)oxy)naphthalen-1-amine (see, for example, Ito,K. et al., WO 2010/112936, 7 Oct. 2010; 3 g, 11.08 mmol) was added to asolution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1 (iv) above; 4.78 g, 12.19 mmol) and TEA (320 μL, 2.296 mmol)in 2-Me-THF (40 mL) and heated at 65° C. (block temperature) for 20 h.Further portions of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (1 g)and TEA (0.1 mL) were added and heating continued for a further 5 h. Theresultant solid was filtered off, washed with iPrOAc then ether toafford the sub-title compound (5.711 g).

¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.16 (s, 1H), 8.96 (s, 1H),8.32 (d, 1H), 8.28 (d, 1H), 8.18 (d, 1H), 8.14 (d, 1H), 7.84 (d, 1H),7.74-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.43 (d, 1H), 7.04-7.02 (m, 2H),6.94 (dd, 1H), 3.80 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 569/571 (M+H)⁺ (ES⁺); 567/569 (M−H)⁻ (ES⁻)

(ii) 2-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)-5-nitrobenzonitrile

2-(2-(2-Methoxyethoxy)ethoxy)ethanol (172 μL, 1.505 mmol) was added to asolution of NaH (60.2 mg, 1.505 mmol) in NMP (5 mL). After stirring for30 min, 2-fluoro-5-nitrobenzonitrile (300 mg, 1.806 mmol) was added tothe reaction mixture. The reaction mixture was stirred at rt for 3 days.The reaction was quenched with a saturated aqueous solution of NH₄Cl (10mL) and extracted with ethyl acetate (10 mL). The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The crude product was purified by chromatography on the Companion (12 gcolumn, 0-10% MeOH in DCM) to afford the sub-title compound (392 mg) asa pale yellow oil.

LCMS m/z 311 (M+H)⁺ (ES⁺)

(iii) 5-Amino-2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzonitrile

To a solution of the product from step (ii) above (390 mg, 1.194 mmol)in EtOH (6 mL) was added Fe powder (667 mg, 11.94 mmol) followed by asolution of NH₄Cl (89 mg, 1.672 mmol) in water (2 mL). The reactionmixture was heated at 80° C. for 1 h. The reaction mixture was cooled tort, filtered through Celite and concentrated in vacuo. The residue wasdissolved in DCM (3 mL), sonicated, filtered, and concentrated in vacuoto afford the sub-title compound (214 mg) as a brown oil.

LCMS m/z 281 (M+H)⁺ (ES⁺). 87% purity

(iv)N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

A mixture of the product from step (iii) above (47 mg, 0.151 mmol), theproduct from step (i) above (100 mg, 0.149 mmol), K₂CO₃ (60 mg, 0.434mmol), and BrettPhos G1 precatalyst (5 mg, 6.26 μmol) were degassedunder vacuum back-filling with nitrogen 3 times. DMF (1 mL) was addedand the suspension degassed under vacuum back-filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 2 h. The reaction was cooled and diluted with water togive a fine suspension. The product was extracted with 10% MeOH:DCM(5×10 mL). The organics were separated, bulked, dried (MgSO₄), filteredand solvent evaporated to give a brown glass. The crude product waspurified by chromatography on the Companion (12 g column, 0-5% MeOH inDCM) to afford a white solid which was purified by preparative HPLC(Varian, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5μm, 19×50 mm column, 35-65% MeCN in Water) to afford a colourless solid.The residue was diluted in DCM (3 mL), washed with a saturated solutionof NaHCO₃ (3 mL), separated via a hydrophobic phase separator, andconcentrated in vacuo to afford the title compound (18 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.15 (s, 1H), 9.03 (s, 1H),8.90 (s, 1H), 8.29 (d, 1H), 8.12-8.09 (m, 4H), 7.85 (d, 1H), 7.69 (dd,1H), 7.62-7.59 (m, 2H), 7.39 (d, 1H), 7.15 (d, 1H), 7.01 (d, 1H), 6.60(dd, 1H), 5.99 (d, 1H), 4.18 (t, 2H), 3.80 (s, 3H), 3.75 (t, 2H),3.61-3.59 (m, 2H), 3.53-3.49 (m, 4H), 3.41-3.39 (m, 2H), 3.21 (s, 3H),3.07 (s, 3H), 1.26 (s, 9H).

LCMS m/z 813 (M+H)⁺ (ES⁺); 811 (M−H)⁻ (ES⁻)

Example 9N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(2-morpholinoethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

(i) 2-(2-Morpholinoethoxy)-5-nitrobenzonitrile

2-Morpholinoethanol (182 μL, 1.505 mmol) was added to a solution of NaH(60 mg, 1.500 mmol) in NMP (5 mL). After stirring 30 min,2-fluoro-5-nitrobenzonitrile (300 mg, 1.806 mmol) was added to thereaction mixture. The reaction was stirred at rt for 3 days. Thereaction was quenched with a saturated aqueous solution of NH₄Cl (10mL), extracted with ethyl acetate (10 mL). The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 0-8% MeOH in DCM) to afford the sub-title compound (285 mg) asan iridescent red crystalline solid.

LCMS m/z 278 (M+H)⁺ (ES⁺)

(ii) 5-Amino-2-(2-morpholinoethoxy)benzonitrile

To a solution of the product from step (i) above (280 mg, 1.010 mmol) inEtOH (6 mL) was added Fe powder (564 mg, 10.10 mmol) followed by asolution of NH₄Cl (76 mg, 1.414 mmol) in water (2 mL). The reactionmixture was heated at 80° C. for 1 h. The reaction mixture was cooled tort, filtered through Celite and concentrated in vacuo to afford thesub-title compound (179 mg) as a yellow solid.

LCMS m/z 248 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((3-cyano-4-(2-morpholinoethoxy)phenyl)amino)pyridin-4-yl)oxy)-naphthalen-1-yl)carbamate

A mixture of the product from step (ii) above (179 mg, 0.680 mmol),tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (seeExample 1(i) above; 255 mg, 0.689 mmol), K₂CO₃ (190 mg, 1.377 mmol) andBrettPhos G1 precatalyst (11 mg, 0.014 mmol) were degassed under vacuum,back-filling with nitrogen 3 times. tBuOH (3 mL) was added and thesuspension degassed an additional 3 times. The reaction was heated undernitrogen at 85° C. for 16 hours. Another aliquot of BrettPhos G1precatalyst (11 mg, 0.014 mmol) was added, and the reaction mixture washeated for further 16 hours at 85° C. The reaction mixture was dilutedwith DCM (20 mL), filtered through Celite and concentrated in vacuo. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 0-10% MeOH in DCM) to afford the sub-title compound (213 mg) asa flocculent brown powder.

LCMS m/z 291 (M+2H)²⁺ (ES⁺); 86% purity

(iv)5-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(2-morpholinoethoxy)-benzonitrile

TFA (2 mL, 26.0 mmol) was added to a solution of the product from step(iii) above (213 mg, 0.366 mmol) in DCM (20 mL) and stirred at rt for 1h. The volatiles were removed under reduced pressure and the residue wasredissolved in DCM (50 mL). The solution was washed with saturatedNaHCO₃ solution (20 mL). The two layers were separated via a hydrophobicphase separator. The organic layer was concentrated in vacuo to affordthe sub-title compound (179 mg) as a flocculent brown solid.

LCMS m/z 241 (M+2H)²⁺ (ES⁺)

(v)N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(2-morpholinoethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

Triethylamine (11 μL, 0.079 mmol) was added to a mixture of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 146 mg, 0.372 mmol) and the product from step (iv)above (179 mg, 0.372 mmol) in isopropyl acetate (10 mL) and the mixtureheated at 70° C. (block temperature) overnight (48 hours). The reactionmixture was concentrated in vacuo. The crude product was purified bychromatography on the Companion (12 g column, 0.5-2% MeOH in DCM,flushed with 20% MeOH in DCM) to afford a tan powder. The crude productwas purified by preparative HPLC (Varian, Acidic (0.1% Formic acid),Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN inWater) to afford a pink oil. The residue was diluted in DCM (3 mL),washed with a saturated solution of NaHCO₃ (3 mL), separated via ahydrophobic phase separator, and concentrated in vacuo to afford thetitle compound (80 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.15 (s, 1H), 9.03 (s, 1H),8.90 (s, 1H), 8.29 (d, 1H), 8.15 (s, 1H), 8.11-8.09 (m, 3H), 7.85 (d,1H), 7.70 (dd, 1H), 7.64-7.59 (m, 2H), 7.39 (d, 1H), 7.15 (d, 1H), 7.01(d, 1H), 6.60 (dd, 1H), 5.99 (d, 1H), 4.17 (t, 2H), 3.80 (s, 3H), 3.55(t, 4H), 3.08 (s, 3H), 2.69 (t, 2H), 1.26 (s, 9H). (4 protons under DMSOand water peak)

LCMS m/z 390 (M+2H)²⁺ (ES⁺)

Example 10N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(3-morpholinopropoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

(i) 2-(3-Morpholinopropoxy)-5-nitrobenzonitrile

3-Morpholinopropan-1-ol (417 μL, 3.01 mmol) was added to a solution ofNaH (120 mg, 3.01 mmol) in NMP (8 mL). After stirring 30 min,2-fluoro-5-nitrobenzonitrile (600 mg, 3.61 mmol) was added to thereaction mixture. The reaction was stirred at rt for 3 days. Thereaction was quenched with a saturated aqueous solution of NH₄Cl (10mL), extracted with ethyl acetate (10 mL). The organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 0-5% Methanol in DCM) to afford the sub-title compound (765 mg)as an iridescent red gum.

LCMS m/z 292 (M+H)⁺ (ES⁺)

(ii) 5-Amino-2-(3-morpholinopropoxy)benzonitrile

To a solution of the product from step (i) above (760 mg, 2.61 mmol) inEtOH (9 mL) was added Fe powder (1457 mg, 26.1 mmol) followed by asolution of NH₄Cl (195 mg, 3.65 mmol) in water (3 mL). The reactionmixture was heated at 80° C. for 1 h. The reaction mixture was cooled tort, filtered through Celite and concentrated in vacuo. The resultingresidue was dissolved in 10% MeOH in DCM (3 mL), sonicated and filtered.The solvents were evaporated to afford the sub-title compound (544 mg)as a sticky yellow gum.

LCMS m/z 262 (M+H)⁺ (ES⁺); 260 (M−H)⁻ (ES⁻)

(iii)N-(5-(tert-Butyl)-3-(3-(4-((2-((3-cyano-4-(3-morpholinopropoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

A mixture of the product from step (ii) above (72 mg, 0.276 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 200 mg, 0.299 mmol), K₂CO₃ (120 mg, 0.868mmol), and BrettPhos G1 precatalyst (10 mg, 0.013 mmol) were degassedunder vacuum back-filling with nitrogen 3 times. DMF (2 mL) was addedand the suspension degassed under vacuum back-filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 17 h. The reaction was cooled and diluted with water togive a fine suspension. The product was extracted with 10% MeOH:DCM(5×10 mL). The organics were separated, bulked, dried (MgSO₄), filteredand solvent evaporated to give a brown glass. The crude product waspurified by chromatography on the Companion (4 g column, 0-10% MeOH inDCM) then purified by preparative HPLC (Gilson, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,40-60% MeCN in Water) to afford the title compound (8 mg) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.17 (bs, 1H), 9.03 (s, 1H),8.90 (s, 1H), 8.29 (d, 1H), 8.13-8.09 (m, 4H), 7.85 (d, 1H), 7.70 (dd,1H), 7.64-7.58 (m, 2H), 7.38 (d, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.60(dd, 1H), 5.99 (d, 1H), 4.09 (t, 2H), 3.80 (s, 3H), 3.55 (t, 4H), 3.05(s, 3H), 2.42 (t, 2H), 2.34 (bs, 4H), 1.86 (tt, 2H), 1.25 (s, 9H).

LCMS m/z 397 (M+2H)2+ (ES⁺), 794 (M+H)⁺ (ES⁺)

Example 11N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfinyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

(i) (2-Methoxy-4-nitrophenyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfane

1-Bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (562 μl, 3.24 mmol) wasadded to a solution of 2-methoxy-4-nitrobenzenethiol (500 mg, 2.70 mmol)and K₂CO₃ (410 mg, 2.97 mmol) in acetone 5 mL. The reaction mixture wasstirred at rt for 17 h. The reaction mixture was concentrated in vacuo,diluted with EtOAc (40 mL), washed with 5 wt % aq NaOH (40 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuoto afford the sub-title compound (1.044 g) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.82 (dd, 1H), 7.62 (d, 1H), 7.27 (d, 1H),3.96 (s, 3H), 3.74 (t, 2H), 3.66-3.61 (m, 6H), 3.53-3.51 (m, 2H), 3.36(s, 3H), 3.18 (t, 2H).

LCMS m/z 354 (M+Na)⁺ (ES⁺); 71% purity

(ii)2-Methoxy-1-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfinyl)-4-nitrobenzene

mCPBA (218 mg, 0.974 mmol) was added slowly to an ice cold solution ofthe product from step (i) above (500 mg, 1.071 mmol) in DCM (5 mL). Thereaction was stirred at 0° C. for 1 h then mCPBA (35 mg, 0.156 mmol)added and stirring at 0° C. continued for a further 10 minutes. Thereaction mixture was filtered cold and the filtrate immediatelypartitioned with sodium bisulphite soln. 20% w/w (5 mL). The organiclayer was separated, washed with sat. NaHCO₃ soln. (5 mL), dried(MgSO₄), filtered and the solvent evaporated to a yellow oil. The crudeproduct was purified by chromatography on silica gel (12 g column, 0%MeOH:EtOAc to 5%) to afford the sub-title compound (380 mg) as a yellowoil.

LCMS m/z 348 (M+H)⁺ (ES⁺)

(iii) 3-Methoxy-4-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfinyl)aniline

A suspension of the product from step (ii) above (380 mg, 1.094 mmol)and 5% Pd/C (75 mg, 50% paste with water) in ethanol (5 mL) was stirredunder hydrogen (5 bar) for 2 h. Another aliquot of 5% Pd/C (75 mg) wasadded, and the mixture was stirred under hydrogen atmosphere (5 bar) for17 hours. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure to yield a pale yellow oil. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 0-5% MeOH in DCM) to afford the sub-title compound (110 mg) as asticky orange oil.

LCMS m/z 318 (M+H)⁺ (ES⁺); 93% purity

(iv)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(2-(2-methoxyethoxy)ethoxy)-ethyl)sulfinyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide

A mixture of the product from step (iii) above (50 mg, 0.158 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 81 mg, 0.143 mmol), K₂CO₃ (60 mg, 0.434 mmol),and BrettPhos G1 precatalyst (4 mg, 5.01 μmol) were degassed undervacuum back-filling with nitrogen 3 times. DMF (1 mL) was added and thesuspension degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 2 h. The reaction was cooled and diluted with water to give a finesuspension. The suspension was filtered to afford a dark red thick gum,which was diluted with DCM, washed with NaHCO₃ (10 mL). The organiclayer was separated via a hydrophobic phase separator then concentratedin vacuo. The crude product was purified by chromatography on theCompanion (4 g column, 0-5% MeOH in DCM) then purified by preparativeHPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 μm, 19×50 mm column, 50-80% MeCN in Water) to afford thetitle compound (31 mg) as a pale brown powder.

¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.25 (s, 1H), 9.13 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.17 (d, 1H), 8.12 (dd, 2H), 7.86 (d, 1H),7.70 (dd, 1H), 7.61 (dd, 1H), 7.53 (s, 1H), 7.41-7.38 (m, 3H), 7.02 (d,1H), 6.63 (dd, 1H), 6.14 (d, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.76-3.73(m, 1H), 3.65-3.61 (m, 1H), 3.50-3.46 (m, 6H), 3.42-3.39 (m, 2H), 3.22(s, 3H), 3.19-3.13 (m, 1H), 3.08 (s, 3H), 2.78-2.72 (m, 1H), 1.26 (s,9H).

LCMS m/z 850 (M+H)⁺ (ES⁺); 848 (M−H)⁻ (ES⁻)

Example 121-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[2-[2-(2-methoxyethoxy)ethoxy]ethylsulfonyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea

(i) (2-Methoxy-4-nitrophenyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfane

1-Bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (303 μL, 1.749 mmol) wasadded to a solution of 2-methoxy-4-nitrobenzenethiol (270 mg, 1.458mmol) and K₂CO₃ (222 mg, 1.604 mmol) in acetone 5 mL. The reactionmixture was stirred at rt for 17 hours. The reaction mixture wasconcentrated in vacuo, diluted with EtOAc (40 mL), washed with 5 wt % aqNaOH (40 mL). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to afford a yellow oil. The crude product waspurified by chromatography on the Companion (12 g column, 0-100% ethylacetate in iso-hexane) to afford the sub-title compound (222 mg) as athick brown oil.

LCMS m/z 354 (M+Na)⁺ (ES⁺)

(ii)2-Methoxy-1-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)-4-nitrobenzene

mCPBA (336 mg, 1.501 mmol) was added slowly to an ice cold solution ofthe product from step (i) above (222 mg, 0.670 mmol) in DCM (5 mL). Thereaction was stirred at 0° C. for 30 min. then allowed to warm to rt andstirred for 1 h. The reaction mixture was filtered and the filtrateimmediately partitioned with sodium bisulphite solution 20% w/w (5 mL).The organic layer was separated, washed with sat. NaHCO₃ soln. (5 mL),dried (MgSO₄), filtered and the solvent evaporated to afford thesub-title compound as a yellow oil.

LCMS m/z 364 (M+H)⁺ (ES⁺)

(iii) 3-Methoxy-4-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)aniline

A suspension of the product from step (ii) above (114 mg, 0.314 mmol)and 5% Pd/C (50% paste with water, 40 mg) in ethanol (5 mL) was stirredunder hydrogen (5 bar) for 2 h. The mixture was filtered, and rechargedwith 5% Pd/C (50% paste with water, 40 mg), stirred under hydrogen (5bar) for 17 h. The catalyst was removed by filtration and the filtratewas concentrated under reduced pressure to yield the sub-title compound(103 mg) as a colourless oil.

LCMS m/z 334 (M+H)⁺ (ES⁺)

(iv)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(2-(2-methoxyethoxy)ethoxy)-ethyl)sulfonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A mixture of the product from step (iii) above (103 mg, 0.309 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 160 mg, 0.281 mmol), K₂CO₃ (90 mg, 0.651 mmol),and BrettPhos G1 precatalyst (6 mg, 7.51 μmol) were degassed undervacuum back-filling with nitrogen 3 times. DMF (1 mL) was added and thesuspension degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 2 h. The reaction mixture was diluted with water (10 mL) forming awhite precipitate. The precipitate was filtered, diluted with DCM (10mL), washed with NaHCO₃ (10 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by chromatographyon the Companion (4 g column, 1-4% MeOH in DCM) then purified bypreparative HPLC (Gilson, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 25-75% MeCN in Water)to afford the title compound (6 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.39 (s, 1H), 9.14 (bs, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.15 (d, 1H), 8.12 (d, 1H),7.85 (d, 1H), 7.73-7.68 (m, 1H), 7.66 (d, 1H), 7.62-7.59 (m, 1H), 7.54(d, 1H), 7.40 (d, 1H), 7.29 (dd, 1H), 7.02 (d, 1H), 6.70 (dd, 1H), 6.18(d, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.61-3.60 (m, 2H), 3.54-3.52 (m,2H), 3.36-3.34 (m, 4H), 3.28-3.24 (m, 4H), 3.16 (s, 3H), 3.07 (s, 3H),1.26 (s, 9H).

LCMS m/z 866 (M+H)⁺ (ES⁺); 864 (M−H)⁻ (ES⁻)

Example 131-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[methyl(3-morpholinopropyl)sulfamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea

(i) 2-Methoxy-N-methyl-N-(3-morpholinopropyl)-4-nitrobenzenesulfonamide

2-Methoxy-4-nitrobenzene-1-sulfonyl chloride (239 mg, 0.948 mmol) inMeCN (3 mL) was added dropwise to an ice-cold solution ofN-methyl-3-morpholinopropan-1-amine (150 mg, 0.948 mmol) and Et₃N (396μL, 2.84 mmol) in MeCN (3 mL). The reaction mixture was allowed to warmto rt and stirred for 1 h. The reaction was concentrated in vacuo, theresidue was diluted with EtOAc (5 mL), filtered and concentrated invacuo to a brown-yellow oil. The crude product was purified bychromatography on the Companion (12 g column, 0-5% MeOH in DCM) toafford the sub-title compound (171 mg) as a sticky yellow oil.

LCMS m/z 374 (M+H)⁺ (ES⁺)

(ii) 4-Amino-2-methoxy-N-methyl-N-(3-morpholinopropyl)benzenesulfonamide

A suspension of the product from step (i) above (171 mg, 0.458 mmol) and5% Pd/C (50% paste with water, 50 mg) in ethanol (5 mL) was stirredunder hydrogen (balloon) for 17 h. The reaction mixture was filteredthrough Celite, concentrated in vacuo to afford the sub-title compound(146 mg) as a pale yellow oil.

LCMS m/z 344 (M+H)⁺ (ES⁺); 342 (M−H)⁻ (ES⁻)

(iii) tert-Butyl(4-((2-((3-methoxy-4-(N-methyl-N-(3-morpholinopropyl)sulfamoyl)phenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 158 mg, 0.425 mmol), the product from step (ii) above (146mg, 0.425 mmol), K₂CO₃ (176 mg, 1.275 mmol), and BrettPhos G1precatalyst (8 mg, 10.01 mol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (1 mL) was added and the suspension degassedunder vacuum back-filling with nitrogen 3 times. The reaction was thenheated under nitrogen at 85° C. (block temperature) for 2 h. Thereaction mixture was diluted with water (10 mL), filtered. The brownsolid was purified by chromatography on the Companion (12 g column,0.5-5% MeOH in DCM) to afford the sub-title compound (50 mg) as a palepurple solid.

LCMS m/z 678 (M+H)⁺ (ES⁺); 676 (M−H)⁻ (ES⁻), 80% purity

(iv)4-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(3-morpholinopropyl)benzenesulfonamide

TFA (0.1 mL, 1.298 mmol) was added to the product from step (iii) above(50 mg, 0.059 mmol) in DCM (1 mL). The reaction mixture was stirred forone hour at rt. The crude mixture was concentrated and loaded onto acolumn of SCX (10 g) in MeOH. The column was washed with MeOH and thenthe product was eluted with 0.7 M ammonia in MeOH. The resultant mixturewas concentrated in vacuo to afford the sub-title compound (41 mg) as apale tan foam.

LCMS m/z 578 (M+H)⁺ (ES⁺), 289 (M+2H)²⁺ (ES⁺); 576 (M−H)⁻ (ES⁻), 89%purity

(v)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(3-morpholinopropyl)benzenesulfonamide

Triethylamine (2 μL, 0.014 mmol) was added to a mixture of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 28 mg, 0.071 mmol) and the product from step (iv)above (41 mg, 0.071 mmol) in isopropyl acetate (5 mL) and the mixtureheated at 70° C. (block temperature) overnight (7 hours). The reactionmixture was concentrated in vacuo. then purified by preparative HPLC(Gilson, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 μm, 19×50 mm column, 25-75% MeCN in Water) to afford thetitle compound (16 mg) as an off-white powder.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (bs, 2H), 9.13 (bs, 1H), 8.91 (s, 1H),8.30 (d, 1H), 8.18-8.17 (m, 2H), 8.12 (d, 1H), 7.86 (d, 1H), 7.73-7.68(m, 1H), 7.63-7.59 (m, 2H), 7.53 (d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H),7.02 (d, 1H), 6.68 (dd, 1H), 6.16 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H),3.52-3.50 (m, 4H), 3.09 (s, 3H), 3.04-3.00 (m, 2H), 2.70 (s, 3H),2.26-2.18 (m, 6H), 1.56 (tt, 2H), 1.26 (s, 9H).

LCMS m/z 876 (M+H)⁺ (ES⁺); 874 (M−H)⁻ (ES⁻)

Example 144-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1-methyl-4-piperidyl)ethyl]benzamide

HATU (80 mg, 0.210 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride (see Example 1 above; 100 mg, 0.136 mmol),2-(1-methylpiperidin-4-yl)ethanamine (27 mg, 0.190 mmol) and Hünig'sBase (100 μL, 0.573 mmol) in DMF (2 mL) at rt. The mixture was stirredfor 2 h then poured into water (10 mL) and partitioned with EtOAc (10mL). The organic phase was concentrated in vacuo. The crude product waspurified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic,Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford a white solid. The solid was partitioned between NaHCO₃solution and 10% MeOH in DCM. The organic phase was dried viahydrophobic frit and concentrated in vacuo. The residue wasre-concentrated from MeCN and the residue dried in vacuo at 45° C. toafford the title compound (53 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.25 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 3H), 7.93 (t, 1H), 7.87 (d,1H), 7.68-7.73 (m, 2H), 7.62 (t, 1H), 7.55 (d, 1H), 7.40 (d, 1H), 7.22(dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.83 (s, 3H), 3.81(s, 3H), 3.28 (q, 2H), 3.10 (s, 3H), 2.73 (d, 2H), 2.12 (s, 3H), 1.80(t, 2H), 1.64 (d, 2H), 1.42 (q, 2H), 1.27 (s, 9H), 1.10-1.22 (m, 3H)

LCMS m/z 824 (M+H)⁺ (ES⁺)

Example 154-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethynyl-N-(2-morpholinoethyl)benzamide

(i) 2-Bromo-N-(2-morpholinoethyl)-4-nitrobenzamide

HATU (4.25 g, 11.18 mmol) was added to a mixture of2-bromo-4-nitrobenzoic acid (2.5 g, 10.16 mmol), 2-morpholinoethanamine(1.600 mL, 12.19 mmol) and Hünig's Base (5 mL, 28.6 mmol) in DMF (30mL). The mixture was stirred at rt for 2 h, a further portion of HATU (1g) added and stirred for 2 h. The mixture was partitioned between EtOAc(200 mL) and water (200 mL), the organic layer washed with sat Na₂CO₃soln (100 mL), brine (100 mL), dried (MgSO₄), filtered and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel (80 g column, 0-5% MeOH/DCM) to afford the sub-title compound(2.36 g) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, 1H), 8.25 (dd, 1H), 7.76 (d, 1H),6.82 (s, 1H), 3.77-3.62 (m, 6H), 2.72 (t, 2H), 2.61 (brs, 4H).

LCMS m/z 358/360 (M+H)⁺ (ES⁺); 356/358 (M−H)⁻ (ES⁻)

(ii)N-(2-morpholinoethyl)-4-nitro-2-((triisopropylsilyl)ethynyl)benzamide

Pd(PPh₃)₄ (0.379 g, 0.328 mmol) was added to a mixture of the productfrom step (i) above (2.35 g, 6.56 mmol), ethynyltriisopropylsilane (2.2mL, 9.81 mmol) and CuI (0.062 g, 0.328 mmol) in Et₃N (10 mL) and DMF (25mL) and heated at 85° C. for 4 h. The mixture was partitioned betweenether (200 mL) and water (200 mL), the organic layer washed with brine(100 mL), dried (MgSO₄), filtered and evaporated under reduced pressure.The residue was purified by chromatography on silica gel (80 g column,0-100% EtOAc/isohexane) then purified further on silica gel (80 gcolumn, 0-3% MeOH/DCM) to afford the sub-title compound (1.737 g) as asolid.

LCMS m/z 460 (M+H)⁺ (ES⁺) at 2.04 min, 90% purity

(iii)4-Amino-N-(2-morpholinoethyl)-2-((triisopropylsilyl)ethynyl)benzamide

A mixture of the product from step (ii) above (1.72 g, 3.74 mmol), Fepowder (2 g, 35.8 mmol) and NH₄Cl (100 mg, 1.869 mmol) in EtOH (20 mL)and water (5 mL) was heated at 80° C. for 3 h then filtered throughCelite. The filtrate was evaporated under reduced pressure and theresidue partitioned between DCM (100 mL) and aq sat NaHCO₃ soln (50 mL).The organic layer was washed with brine (50 mL), dried (MgSO₄), filteredand evaporated under reduced pressure. The crude product was purified bychromatography on silica gel (80 g column, 0-5% MeOH/DCM) to afford thesub-title compound (1.23 g) as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, 1H), 7.87 (brs, 1H), 6.80 (d, 1H),6.71 (dd, 1H), 3.97 (s, 2H), 3.74 (brs 4H), 3.63-3.58 (m, 2H), 2.65-2.52(brm, 6H), 1.19-1.15 (m, 21H).

LCMS m/z 430 (M+H)⁺ (ES⁺)

(iv) tert-Butyl(4-((2-((4-((2-morpholinoethyl)carbamoyl)-3-((triisopropylsilyl)ethynyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

BrettPhos G1 Precatalyst (68 mg, 0.085 mmol) was added to a mixture oftert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (seeExample 1(i) above; 785 mg, 2.118 mmol), the product from step (iii)above (910 mg, 2.118 mmol) and K₂CO₃ (600 mg, 4.34 mmol) in DMF (5 mL)and heated at 80° C. for 4 h. A further portion of BrettPhos G1Precatalyst (68 mg, 0.085 mmol) was added, stirred for 20 h at 80° C.then partitioned between EtOAc (100 mL) and water (50 mL). The organiclayer was washed with brine (50 mL), dried (MgSO₄), filtered andevaporated under reduced pressure. The crude product was purified bychromatography on silica gel (80 g column, EtOAc) to afford thesub-title compound (580 mg) as a yellow foam.

¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, 1H), 8.00-7.95 (m, 3H), 7.88-7.81 (m,2H), 7.63-7.51 (m, 3H), 7.46 (dd, 1H), 7.22 (d, 1H), 6.90 (s, 1H), 6.70(s, 1H), 6.50 (dd, 1H), 6.26 (d, 1H), 3.76-3.74 (m, 4H), 3.65-3.60 (m,2H), 2.68-2.52 (m, 6H), 1.60 (s, 9H), 1.18-1.16 (m, 21H).

LCMS m/z 764 (M+H)⁺ (ES⁺)

(v)4-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-2-((triisopropylsilyl)ethynyl)benzamide

TFA (2 mL, 26.0 mmol) was added to a solution of the product from step(iv) above (570 mg, 0.746 mmol) in DCM (10 mL), the mixture stirred for4 h then evaporated under reduced pressure. The residue was partitionedbetween DCM (50 mL) and sat aq NaHCO₃ soln (20 mL), the organic layerwashed with brine (20 mL), dried (MgSO₄), filtered and evaporated underreduced pressure to afford the sub-title compound (474 mg) as a lightbrown foam.

LCMS m/z 664 (M+H)⁺ (ES⁺)

(vi)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-2-((triisopropylsilyl)ethynyl)benzamide

A mixture of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 167 mg, 0.425 mmol), the product from step (v)above (235 mg, 0.354 mmol) and Et₃N (15 μL, 0.108 mmol) in iPrOAc (5 mL)was heated at 60° C. for 6 h then evaporated under reduced pressure. Thecrude product was purified by chromatography on silica gel (40 g column,0-5% MeOH/DCM) to afford the sub-title compound (254 mg) as a foam.

LCMS m/z 962.5 (M+H)⁺ (ES⁺), 80% purity

(vii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethynyl-N-(2-morpholinoethyl)benzamide

TBAF (300 μL, 0.300 mmol, 1 M in THF) was added to a stirred solution ofthe product from step (vi) above (250 mg, 0.208 mmol) in THF (2 mL). Themixture was stirred at rt for 3 h then partitioned between EtOAc (50 mL)and sat aq NaHCO₃ (30 mL). The organic layer was dried (MgSO₄), filteredand evaporated under reduced pressure. The residue was purified bychromatography on silica gel (40 g column, 0-5% MeOH/DCM) then bypreparative HPLC (Gilson, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-70% MeCN in Water)to afford a foam that was slurried in ether, filtered then dried toafford the title compound (91 mg) as a solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.24 (s, 1H), 9.15 (s, 1H),8.91 (s, 1H), 8.30 (s, 1H), 8.19-8.17 (m, 2H), 8.12 (d, 1H), 8.05-8.02(dd, 1H), 7.96 (d, 1H), 7.87 (d, 1H), 7.72 (dd, 1H), 7.64-7.57 (m, 2H),7.48 (d, 1H), 7.41 (d, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.12 (d, 1H),4.35 (s, 1H), 3.81 (s, 3H), 3.60-3.56 (m, 4H), 3.10 (s, 3H), 2.47-2.37(m, 6H), 1.27 (s, 9H). 2H under water peak at 3.33

LCMS m/z 806 (M+H)⁺ (ES⁺); 804 (M−H)⁻ (ES⁻)

Example 164-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]-2-methoxy-benzamide

HATU (80 mg, 0.210 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 100 mg, 0.136 mmol),2-(2-(2-aminoethoxy)ethoxy)ethanol (28 mg, 0.188 mmol) and Hünig's Base(100 μL, 0.573 mmol) in DMF (2 mL) at rt. The mixture was stirred forovernight then poured into water (10 mL) and partitioned with EtOAc (10mL). The organic phase was concentrated in vacuo. The residue waspurified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic,Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford a pale pink solid. The solid was partitioned between NaHCO₃solution and 10% MeOH in DCM. The organic phase was dried viahydrophobic frit and concentrated in vacuo. The residue wasre-concentrated from MeCN and the residue dried in vacuo at 45° C. toafford the title compound (58 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.09-8.19 (m, 4H), 7.87 (d, 1H), 7.76 (d,1H), 7.69-7.73 (m, 1H), 7.59-7.64 (m, 2H), 7.40 (d, 1H), 7.23 (dd, 1H),7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.57 (t, 1H), 3.86 (s, 3H),3.81 (s, 3H), 3.43-3.55 (m, 12H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 831 (M+H)⁺ (ES⁺)

Example 17

The following compounds were prepared by methods analogous to thosedescribed above. Where chemical shifts from ¹H NMR spectra are reported,these were obtained at 400 MHz and ambient temperature, unless otherwisespecified.

(a)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H),8.84 (s, 1H), 8.31 (d, 1H), 8.20 (t, 1H), 8.17 (d, 1H), 8.12 (d, 1H),8.03 (s, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.71 (t, 1H), 7.61 (t, 1H),7.56 (s, 1H), 7.40 (d, 1H), 7.24 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H),6.16 (d, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.37 (q, 2H), 2.97 (s, 3H),2.25-2.46 (m, 10H), 2.17 (s, 3H), 1.26 (s, 9H).

LCMS m/z 413 (M+2H)²⁺ (ES⁺)

(b)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(3-morpholinopropyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.89 (s, 1H), 8.30 (d, 1H), 8.11-8.17 (m, 3H), 7.98 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.61 (t, 1H), 7.56 (d, 1H), 7.40 (d, 1H), 7.22(dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.83 (s, 3H), 3.81(s, 3H), 3.55-3.57 (m, 4H), 3.29 (q, 2H), 3.05 (s, 3H), 2.29-2.34 (m,6H), 1.65 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(c)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[(2S,6R)-2,6-dimethylmorpholin-4-yl]ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.21 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.24 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.86 (s, 3H), 3.81 (s,3H), 3.55-3.62 (m, 2H), 3.39 (q, 2H), 3.10 (s, 3H), 2.79 (d, 2H), 2.44(t, 2H), 1.66 (t, 2H), 1.27 (s, 9H), 1.07 (d, 6H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(d)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.08-8.19 (m, 4H), 8.87 (d, 1H), 7.78 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 1H), 7.58 (d, 1H), 7.40 (d, 1H),7.23 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.86 (s, 3H),3.81 (s, 3H), 3.61-3.64 (m, 2H), 3.39 (q, 2H), 3.10 (s, 3H), 2.41 (t,2H), 2.34 (bs, 2H), 2.20 (s, 2H), 1.27 (s, 9H), 1.17 (s, 6H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(e)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-morpholino-2-oxo-ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.31 (s, 1H), 9.17 (s, 1H),8.93 (s, 1H), 8.58 (t, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 8.18 (d, 1H),8.13 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H), 7.72 (t, 1H), 7.60-7.64 (m,2H), 7.41 (d, 1H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.16 (d,1H), 4.18 (d, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.57-3.61 (m, 4H),3.43-3.49 (m, 4H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(f)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-methyl-1,4-diazepan-1-yl)ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.11-8.17 (m, 4H), 7.87 (d, 1H), 7.78 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.58 (d, 1H), 7.40 (d, 1H), 7.23 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.87 (s, 3H), 3.81 (s,3H), 2H under water, 3.09 (s, 3H), 2.65-2.70 (m, 4H), 2.51-2.59 (m, 6H),2.25 (s, 3H), 1.73 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 420 (M+2H)²⁺ (ES⁺)

(g)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-2-[2-(2-methoxyethoxy)ethoxy]-1-methyl-ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.28 (s, 1H), 9.17 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H),7.96 (d, 1H), 7.87 (d, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 7.63 (d, 1H),7.59 (d, 1H), 7.41 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H),6.15 (d, 1H), 4.06-4.15 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.51-3.55(m, 6H), 3.45-3.49 (m, 1H), 3.39-3.43 (m, 3H), 3.22 (s, 3H), 3.10 (s,3H), 1.27 (s, 9H), 1.15 (d, 3H).

LCMS m/z 859 (M+H)⁺ (ES⁺)

(h)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-2-[2-(2-methoxyethoxy)ethoxy]-1-methyl-ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.28 (s, 1H), 9.17 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H),7.96 (d, 1H), 7.87 (d, 1H), 7.75 (d, 1H), 7.71 (d, 1H), 7.63 (d, 1H),7.59 (d, 1H), 7.41 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H),6.15 (d, 1H), 4.06-4.15 (m, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.51-3.55(m, 6H), 3.45-3.49 (m, 1H), 3.39-3.43 (m, 3H), 3.22 (s, 3H), 3.10 (s,3H), 1.27 (s, 9H), 1.15 (d, 3H).

LCMS m/z 859 (M+H)⁺ (ES⁺)

(i)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]pyrimidin-2-yl]amino]-2-methoxy-N-(2-morpholinoethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.42 (s, 1H), 9.16 (s, 1H),8.95 (s, 1H), 8.48 (d, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 8.16-8.12 (m,2H), 7.85 (d, 1H), 7.72-7.68 (m, 1H), 7.62-7.55 (m, 2H), 7.43 (d, 1H),7.35 (s, 1H), 7.08 (brd, 1H), 7.02 (d, 1H), 6.68 (d, 1H), 3.82 (s, 3H),3.60-3.52 (m, 7H), 3.10 (s, 3H), 2.43-2.33 (m, 6H), 1.27 (s, 9H). 2Hunderwater

LCMS m/z 813 (M+H)⁺ (ES⁺); 811 (M−H)⁻ (ES⁻)

(j)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(1-methyl-4-piperidyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1H), 9.27 (s, 1H), 9.19 (bs, 1H),8.91 (s, 1H), 8.31 (d, 1H), 8.11-8.17 (m, 3H), 7.86 (d, 1H), 7.80 (d,1H), 7.68-7.78 (m, 2H), 7.58-7.63 (m, 2H), 7.40 (d, 1H), 7.22 (d, 1H),7.03 (d, 1H), 6.66 (dd, 1H), 6.14 (d, 1H), 3.85 (s, 3H), 3.81 (s, 3H),3.70-3.77 (m, 1H), 3.07 (s, 3H), 2.61-2.63 (m, 2H), 2.16 (s, 3H), 2.04(t, 2H), 1.78-1.81 (m, 2H), 1.52 (q, 2H), 1.26 (s, 9H).

LCMS m/z 796 (M+H)⁺ (ES⁺)

(k)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.12-8.20 (m, 4H), 7.87 (d, 1H), 7.79 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.58 (d, 1H), 7.41 (d, 1H), 7.23 (dd,1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.15 (d, 1H), 3.88 (s, 3H), 3.81 (s,3H), 3.60-3.63 (m, 2H), 3.31 (q, 2H), 3.25 (s, 2H), 3.10 (s, 3H), 4Hunder DMSO, 1.27 (s, 9H), 0.94 (s, 6H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(l)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-thiomorpholinoethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.12-8.19 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.41 (d, 1H), 7.23 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.87 (s, 3H), 3.81 (s,3H), 3.37 (q, 2H), 3.10 (s, 3H), 2.68-2.69 (m, 4H), 2.63-2.64 (m, 4H),2H under DMSO, 1.27 (s, 9H).

LCMS m/z 828 (M+H)⁺ (ES⁺)

(m)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-hydroxy-1-piperidyl)ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.23 (t, 1H), 8.11-8.19 (m, 3H), 7.87 (d,1H), 7.77 (d, 1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.40 (d,1H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 4.59 (d,1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.43-3.48 (m, 1H), 2H under H₂O, 3.10(s, 3H), 2.68-2.75 (m, 2H), 2.42 (t, 2H), 2.05 (t, 2H), 1.73-1.76 (m,2H), 1.40 (q, 2H), 1.27 (s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(n)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-methyl-2-morpholino-propyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.29 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.25 (t, 1H), 8.12-8.19 (m, 3H), 7.87 (d,1H), 7.81 (d, 1H), 7.71 (t, 1H), 7.60-7.64 (m, 2H), 7.41 (d, 1H), 7.24(dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 3.93 (s, 3H), 3.81(s, 3H), 3.61 (bs 4H), 3.26 (d, 2H), 3.10 (s, 3H), 4H under DMSO, 1.27(s, 9H), 1.00 (s, 6H)

LCMS m/z 840 (M+H)⁺ (ES⁺)

(o)1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-[methyl(2-morpholinoethyl)sulfamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]urea

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.39 (s, 1H), 9.13 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.18-8.17 (m, 2H), 8.12 (d, 1H), 7.86 (d,1H), 7.73-7.68 (m, 1H), 7.63-7.60 (m, 2H), 7.54 (d, 1H), 7.40 (d, 1H),7.24 (dd, 1H), 7.02 (d, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 3.80 (s, 3H),3.79 (s, 3H), 3.52-3.50 (m, 4H), 3.15-3.11 (m, 2H), 3.09 (s, 3H), 2.73(s, 3H), 2.38 (t, 2H), 2.33-2.31 (m, 4H), 1.26 (s, 9H).

LCMS m/z 862 (M+H)⁺ (ES⁺); 860 (M−H)⁻ (ES⁻)

(p)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1-piperidyl)ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.23 (t, 1H), 8.12-8.19 (m, 3H), 7.87 (d,1H), 7.78 (d, 1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (s, 1H), 7.41 (d,1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.86 (s,3H), 8.31 (s, 3H), 2H under H₂O, 3.10 (s, 3H), 2.30-2.43 (m, 6H),1.47-1.58 (m, 4H), 1.35-1.46 (m, 2H), 1.27 (s, 9H)

LCMS m/z 810 (M+H)⁺ (ES⁺)

(q)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-pyrrolidin-1-ylethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.22 (t, 1H), 8.12-8.19 (m, 3H), 7.87 (d,1H), 7.76 (d, 1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.56 (d, 1H), 7.40 (d,1H), 7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.83 (s,3H), 3.81 (s, 3H), 2H under H₂O, 3.10 (s, 3H), 2.56 (t, 2H), 4H underDMSO, 1.71 (bs, 4H), 1.27 (s, 9H)

LCMS m/z 796 (M+H)⁺ (ES⁺)

(r)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.30 (d, 1H), 8.10-8.19 (m, 4H), 7.87 (d, 1H), 7.70-7.76(m, 2H), 7.62 (t, 1H), 7.57 (s, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.03(d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2Hunder H₂O, 3.10 (s, 3H), 3.05-3.14 (m, 4H), 2.93-3.01 (m, 4H), 2.65 (t,2H), 1.27 (s, 9H)

LCMS m/z 860 (M+H)⁺ (ES⁺)

(s)5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.67 (bs, 1H), 9.52(s, 1H), 9.14 (s, 1H), 8.98 (s, 1H), 8.35 (d, 1H), 8.18 (d, 1H),8.12-8.15 (m, 2H), 8.02 (t, 1H), 7.87 (d, 1H), 7.70-7.74 (m, 2H),7.62-7.65 (m, 1H), 7.41-7.44 (m, 2H), 7.12 (d, 1H), 7.03 (d, 1H), 6.75(d, 1H), 6.23 (d, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.26 (q, 2H), 3.10(s, 3H), 2.25 (t, 2H), 1.47-1.55 (m, 4H), 1.27 (s, 9H).

LCMS (of hydrochloride salt) m/z 799 (M+H)⁺ (ES⁺); 797 (M−H)⁻ (ES⁻)

(t)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.40 (s, 1H), 9.33 (s, 1H),9.14 (s, 1H), 8.92 (s, 1H), 8.30 (d, 1H), 8.20-8.15 (m, 2H), 8.12 (d,1H), 7.91-7.85 (m, 1H), 7.79 (d, 2H), 7.75-7.67 (m, 3H), 7.62 (ddd, 1H),7.41 (d, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.17 (d, 1H), 3.81 (s, 3H),3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 670 (M+H)⁺ (ES⁺); 668 (M−H)⁻ (ES⁻)

(u)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-(2-morpholinoethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.20 (s, 1H), 9.13 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.19-8.08 (m, 4H), 7.87 (d, 1H), 7.75-7.58(m, 6H), 7.40 (d, 1H), 7.03 (d, 1H), 6.64 (dd, 1H), 6.15 (d, 1H), 3.81(s, 3H), 3.57 (t, 4H), 3.35 (d, 2H), 3.08 (s, 3H), 2.43 (dd, 6H), 1.27(s, 9H).

LCMS 782 (M+H)⁺ (ES⁺); 780 (M−H)⁻ (ES⁻)

(v)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-1-methyl-2-morpholino-ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.25 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.17 (d, 1H), 8.12 (d, 1H),7.98 (d, 1H), 7.87 (d, 1H), 7.69-7.74 (m, 2H), 7.60-7.64 (m, 1H), 7.58(d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15(d, 1H), 4.01-4.08 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.54-3.60 (m,4H), 3.10 (s, 3H), 2.39-2.43 (m, 5H), 2.31 (dd, 1H), 1.27 (s, 9H), 1.16(d, 3H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(w)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-piperazin-1-ylethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H),8.31 (d, 1H), 8.22 (t, 1H), 8.11-8.18 (m, 3H), 7.87 (d, 1H), 7.78 (d,1H), 7.71 (t, 1H), 7.58-7.63 (m, 2H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.03(d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 5Hunder water, 3.09 (s, 3H), 2.72-2.74 (m, 3H), 2.42 (t, 2H), 2.35 (bs,4H), 1.27 (s, 9H)

LCMS m/z 811 (M+H)⁺ (ES⁺)

(x)3-[2-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethoxy]ethoxy]propanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.45 (s, 1H), 9.27 (s, 1H), 8.95 (s, 1H),8.31 (d, 1H), 8.08-8.18 (m, 4H), 7.87 (d, 1H), 7.76 (d, 1H), 7.71 (t,1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.22 (dd, 1H), 7.03 (d,1H), 6.67 (dd, 1H), 6.17 (d, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.60-3.64(m, 2H), 3.50-3.53 (m, 6H), 3.43 (q, 2H), 3.10 (s, 3H), 2.42-2.45 (m,2H), 1.27 (s, 9H).

LCMS m/z 859 (M+H)⁺ (ES⁺)

(y)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(4-morpholinobutyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.16 (d, 1H), 8.12 (d, 1H),7.95 (t, 1H), 7.87 (d, 1H), 7.68-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.56(d, 1H), 7.40 (d, 1H), 7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16(d, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.54-3.56 (m, 4H), 3.26 (q, 2H),3.10 (s, 3H), 2.25-2.32 (m, 6H), 1.43-1.53 (m, 4H), 1.27 (s, 9H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(z)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.22 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (s, 1H), 7.40 (d, 1H), 7.24 (d,1H), 7.03 (s, 1H), 6.66 (d, 1H), 6.16 (s, 1H), 4.37 (t, 1H), 3.88 (s,3H), 3.81 (s, 3H), 3.50 (q, 2H), 2H under H₂O, 3.10 (s, 3H), 2.37-2.44(m, 12H), 1.27 (s, 9H)

LCMS m/z 855 (M+H)⁺ (ES⁺)

(aa)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(4-methylpiperazin-1-yl)propyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.17 (d, 1H), 8.12 (d, 1H),7.97 (t, 1H), 7.87 (d, 1H), 7.69-7.73 (m, 2H), 7.60-7.64 (m, 1H), 7.55(s, 1H), 7.40 (d, 1H), 7.22 (d, 1H), 7.03 (d, 1H), 6.65 (dd, 1H), 6.15(d, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2H under water, 3.10 (s, 3H),2.22-2.40 (m, 10H), 2.14 (s, 3H), 1.64 (quint, 2H), 1.27 (s, 9H)

LCMS m/z 839 (M+H)⁺ (ES⁺)

(ab)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-methyl-N-(2-morpholinoethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.14 (s, 1H), 9.07 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.11-8.14 (m, 2H), 7.87 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.38-7.40 (m, 2H), 7.21 (d, 1H), 7.03(d, 1H), 6.97 (t, 1H), 6.62 (dd, 1H), 6.12 (s, 1H), 3.81 (s, 3H), 3.70(s, 3H, rotamer 1), 3.69 (s, 3H, rotamer 2), 3.56-3.59 (m, 2H),3.44-3.54 (m, 3H), 3.10-3.23 (bs, 1H), 3.10 (s, 3H), 2.93 (s, 3H,rotamer 1), 2.76 (s, 3H, rotamer 2), 2.38-2.48 (m, 3H), 2.26-2.38 (bs,1H), 2.10-2.19 (m, 2H), 1.27 (s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(ac)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-hydroxyethyl(methyl)amino]ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.11-8.19 (m, 4H), 7.87 (d, 1H), 7.76 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.58 (d, 1H), 7.40 (d, 1H), 7.23 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.38 (t, 1H), 3.85 (s,3H), 3.81 (s, 3H), 3.51 (q, 2H), 2H under water, 3.10 (s, 3H), 4H underDMSO, 2.24 (s, 3H), 1.27 (s, 9H).

LCMS m/z 800 (M+H)⁺ (ES⁺)

(ad)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-[2-methoxyethyl(methyl)amino]ethyl]-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.11-8.19 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.58 (d, 1H), 7.40 (d, 1H), 7.22 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.85 (s, 3H), 3.81 (s,3H), 3.44 (t, 2H), 2H under water, 3.23 (s, 3H), 3.10 (s, 3H), 2.54-2.57(m, 2H), 2H under DMSO, 2.24 (s, 3H), 1.27 (s, 9H).

LCMS m/z 814 (M+H)⁺ (ES⁺)

(ae)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-N-(2-morpholinoethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.14 (s, 1H), 9.02 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.11-8.14 (m, 2H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.39 (d, 1H), 7.03 (d, 1H),6.93 (s, 2H), 6.62 (dd, 1H), 6.12 (d, 1H), 3.81 (s, 3H), 3.61 (s, 6H),3.55-3.57 (m, 4H), 3.23 (q, 2H), 3.10 (s, 3H), 2.34-2.40 (m, 6H), 1.27(s, 9H).

LCMS m/z 842 (M+H)⁺ (ES⁺)

(af)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-methyl-N-(3-morpholinopropyl)benzamide

¹H NMR (400 MHz, DMSO-d6, 90° C.) δ: 9.17 (s, 1H), 8.83 (s, 1H),8.63-8.69 (m, 2H), 8.29 (d, 1H), 8.12-8.13 (m, 2H), 8.04 (d, 1H), 7.93(d, 1H), 7.66-7.70 (m, 1H), 7.58-7.62 (m, 1H), 7.40 (d, 1H), 7.34 (d,1H), 7.18 (dd, 1H), 7.08 (d, 1H), 6.96 (d, 1H), 6.56 (dd, 1H), 6.27 (d,1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.41-3.61 (bm, 4H), 3.10 (s, 3H), 2.85(bs, 3H), 2.00-2.46 (bm, 8H), 1.55-1.75 (bm, 2H), 1.30 (s, 9H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(ag)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-pyridyl]amino]-2-methoxy-N-[3-(1-oxo-1,4-thiazan-4-yl)propyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.18 (m, 3H), 7.98 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.84 (s, 3H),3.81 (s, 3H), 2H underwater, 3.10 (s, 3H), 2.81-2.90 (m, 4H), 2.62-2.73(m, 4H), 2.40 (t, 2H), 1.67 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 858 (M+H)⁺ (ES⁺)

(ah)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[3-(1,1-dioxo-1,4-thiazinan-4-yl)propyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 3H), 7.98 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.60-7.64 (m, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.84 (s, 3H),3.81 (s, 3H), 2H under water, 3.10 (s, 3H), 3.06-3.08 (m, 4H), 2.83-2.92(m, 4H), 2H under DMSO, 1.66 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 874 (M+H)⁺ (ES⁺)

(ai)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(1,4-oxazepan-4-yl)ethyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.36 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.21 (m, 4H), 7.87 (d, 1H), 7.78 (d,1H), 7.71 (t, 1H), 7.62 (t, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.23 (dd,1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.87 (s, 3H), 3.81 (s,3H), 3.69 (t, 2H), 3.62-3.64 (m, 2H), 2H underwater, 3.10 (s, 3H),2.67-2.70 (m, 4H), 2.62 (t, 2H), 1.81 (quint, 2H), 1.27 (s, 9H).

LCMS 826 (M+H)⁺ (ES⁺)

(aj)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(1,4-oxazepan-4-yl)propyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 3H), 7.98 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.60-7.64 (m, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.84 (s, 3H),3.81 (s, 3H), 3.66 (t, 2H), 3.58-3.60 (m, 2H), 2H underwater, 3.10 (s,3H), 2.59-2.63 (m, 4H), 2H under DMSO, 1.78 (quint, 2H), 1.64 (quint,2H), 1.27 (s, 9H).

LCMS 840 (M+H)⁺ (ES⁺)

(ak)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1-methyl-4-piperidyl)methyl]benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.24 (s, 1H), 9.11 (s, 1H),8.91 (s, 1H), 8.31 (d, 1H), 8.11-8.19 (m, 3H), 7.96 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.57 (d, 1H), 7.40 (d, 1H),7.21 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.84 (s, 3H),3.81 (s, 3H), 3.16 (t, 2H), 3.10 (s, 3H), 2.74 (bd, 2H), 2.13 (s, 3H),1.77-1.82 (m, 2H), 1.60 (bd, 2H), 1.42-1.47 (bm, 1H), 1.27 (s, 9H),1.15-1.22 (m, 2H).

LCMS m/z 810 (M+H)⁺ (ES⁺)

(al)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4,4-difluoro-1-piperidyl)ethyl]-2-methoxy-benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 4H), 7.87 (d, 1H), 7.76 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.64 (m, 1H), 7.57 (d, 1H), 7.40 (d, 1H),7.24 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.85 (s, 3H),3.81 (s, 3H), 3.39 (q, 2H), 3.10 (s, 3H), 2.54-2.64 (m, 6H), 1.92-2.01(m, 4H), 1.27 (s, 9H).

LCMS m/z 846 (M+H)⁺ (ES⁺)

(am)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1H), 9.41 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.31 (d, 1H), 8.19-8.21 (m, 2H), 8.13 (d, 1H), 7.95 (d,1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.72 (t, 1H), 7.62 (t, 1H), 7.52 (dd,1H), 7.41 (d, 1H), 7.03 (d, 1H), 6.70 (dd, 1H), 6.17 (d, 1H), 3.81 (s,3H), 3.10 (s, 3H), 2.71 (s, 6H), 1.27 (s, 9H).

LCMS m/z 713 (M+H)⁺ (ES⁺)

(an)4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.77 (s, 1H), 9.41 (s, 1H), 9.16 (bs, 1H),8.93 (s, 1H), 8.48 (d, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),7.84-7.88 (m, 2H), 7.67-7.71 (m, 1H), 7.58-7.62 (m, 1H), 7.47 (d, 1H),7.42 (d, 1H), 7.33 (s, 1H), 7.06 (d, 1H), 7.03 (d, 1H), 6.68 (d, 1H),3.82 (s, 3H), 3.51 (s, 3H), 3.23 (q, 2H), 3.09 (s, 3H), 2.70 (bd, 2H),2.10 (s, 3H), 1.77 (t, 2H), 1.61 (d, 2H), 1.38 (q, 2H), 1.27 (s, 9H),1.06-1.17 (m, 3H).

LCMS m/z 825 (M+H)⁺ (ES⁺)

(ao)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(3-morpholinopropyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.42 (s, 1H), 9.16 (s, 1H),8.95 (s, 1H), 8.49 (d, 1H), 8.31 (d, 1H), 8.21 (d, 1H), 8.13 (d, 1H),7.98-7.91 (br m, 1H), 7.86 (d, 1H), 7.72-7.68 (m, 1H), 7.63-7.59 (m,1H), 7.50 (d, 1H), 7.44 (d, 1H), 7.35 (s, 1H), 7.11-7.05 (br m, 1H),7.04 (d, 1H), 6.69 (d, 1H), 3.83 (s, 3H), 3.59-3.49 (m, 7H), 3.28-3.22(m, 2H), 3.02 (s, 3H), 2.37-2.24 (m, 6H), 1.66-1.58 (m, 2H), 1.28 (s,9H).

LCMS m/z 827 (M+H)⁺ (ES⁺); 825 (M−H)⁻ (ES⁻)

(ap)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.77 (s, 1H), 9.40 (s, 1H), 9.15 (bs, 1H),8.92 (s, 1H), 8.48 (d, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H),7.91 (t, 1H), 7.85 (d, 1H), 7.67-7.71 (m, 1H), 7.58-7.62 (m, 1H), 7.49(d, 1H), 7.42 (d, 1H), 7.33 (s, 1H), 7.07 (bd, 1H), 7.03 (d, 1H), 6.68(d, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.23 (q, 2H), 3.10 (s, 3H),2.18-2.44 (bm, 10H), 2.11 (s, 3H), 1.59 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 840 (M+H)⁺ (ES⁺); 421 (M+2H)²⁺ (ES⁺)

(aq)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 9.41 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.48 (d, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.11-8.15 (m,2H), 7.86 (d, 1H), 7.67-7.71 (m, 1H), 7.57-7.62 (m, 2H), 7.43 (d, 1H),7.36 (s, 1H), 7.08 (d, 1H), 7.03 (d, 1H), 6.69 (d, 1H), 3.82 (s, 3H),3.52 (s, 3H), 2H under water, 3.10 (s, 3H), 2.24-2.42 (m, 10H), 2.14 (s,3H), 1.27 (s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(ar)2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)aceticacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 9.49(s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 8.33-8.39 (m, 2H), 8.13-8.19 (m,3H), 7.87 (d, 1H), 7.82 (d, 1H), 7.72 (t, 1H), 7.63 (t, 1H), 7.50 (s,1H), 7.43 (d, 1H), 7.16 (d, 1H), 7.03 (d, 1H), 6.74 (dd, 1H), 6.23 (dd,1H), 3.97 (d, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.10 (s, 3H), 1.27 (s,9H).

LCMS (of hydrochloride salt) m/z 757 (M+H)⁺ (ES⁺)

(as)4-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)butanoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 9.49(s, 1H), 9.14 (s, 1H), 8.96 (s, 1H), 8.34 (d, 1H), 8.18 (d, 1H), 8.15(d, 1H), 8.13 (s, 1H), 8.04 (t, 1H), 7.87 (d, 1H), 7.70-7.74 (m, 2H),7.61-7.65 (m, 1H), 7.42-7.44 (m, 2H), 7.13 (d, 1H), 7.03 (d, 1H), 6.74(dd, 1H), 6.22 (d, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.28 (q, 2H), 3.10(s, 3H), 2.25 (t, 2H), 1.73 (quint, 2H), 1.27 (s, 9H).

LCMS (of hydrochloride salt) m/z 785 (M+H)⁺ (ES⁺)

(at)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.01 (s, 1H), 8.91 (s, 1H),8.30 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H), 8.11 (d, 1H), 7.87 (d, 1H),7.76 (t, 1H), 7.73-7.67 (m, 1H), 7.65-7.55 (m, 1H), 7.39 (d, 1H), 7.03(d, 1H), 6.92 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H), 3.81 (s, 3H), 3.61(s, 6H), 3.14 (q, 2H), 3.09 (s, 3H), 2.79-2.66 (m, 2H), 2.12 (s, 3H),1.86-1.69 (m, 2H), 1.70-1.57 (m, 2H), 1.41-1.29 (m, 3H), 1.27 (s, 9H),1.17-0.98 (m, 2H).

LCMS m/z 854 (M+H)⁺ (ES⁺)

(au)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.12 (s, 1H), 9.01 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.13 (d, 1H), 8.12 (d, 1H),7.87 (d, 1H), 7.83 (t, 1H), 7.75-7.66 (m, 1H), 7.65-7.52 (m, 1H), 7.39(d, 1H), 7.03 (d, 1H), 6.92 (s, 2H), 6.61 (dd, 1H), 6.12 (d, 1H), 3.81(s, 3H), 3.61 (s, 6H), 3.13 (q, 2H), 3.09 (s, 3H), 2.48-2.14 (m, 10H),2.11 (s, 3H), 1.56 (p, 2H), 1.27 (s, 9H).

LCMS m/z 869 (M+H)⁺ (ES⁺)

(av)(S)-2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-(1H-imidazol-4-yl)propanoicacid

¹H NMR (of dihydrochloride salt; 400 MHz, DMSO-d6) δ: 14.48 (s, 1H),14.29 (s, 1H), 9.98 (bs, 1H), 9.76 (s, 1H), 9.13 (s, 1H), 9.10 (s, 1H),9.02 (s, 1H), 8.43 (d, 1H), 8.37 (d, 1H), 8.12-8.16 (m, 3H), 7.86 (d,1H), 7.69-7.73 (m, 2H), 7.61-7.65 (m, 1H), 7.40-7.44 (m, 3H), 7.10 (d,1H), 7.03 (d, 1H), 6.79 (d, 1H), 6.31 (s, 1H), 4.80 (q, 1H), 3.83 (s,3H), 3.82 (s, 3H), 3.18-3.31 (m, 2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS (of dihydrochloride salt) m/z 837 (M+H)⁺ (ES⁺)

(aw)(S)-1-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoyl)pyrrolidine-2-carboxylicacid

2:1 mixture of rotamers. ¹H NMR (of hydrochloride salt; 400 MHz,DMSO-d6) δ: 10.00 (bs, 1H), 9.61 (s, 1H), 9.14 (s, 1H), 9.03 (s, 1H),8.38 (d, 1H), 8.15-8.17 (m, 2H), 8.08 (d, 1H, major rotamer), 8.07 (d,1H, minor rotamer), 7.86 (d, 1H), 7.71-7.75 (m, 1H), 7.63-7.67 (m, 1H),7.46 (d, 1H, major rotamer), 7.45 (d, 1H, minor rotamer), 7.18 (s, 1H),7.12 (d, 1H), 7.96-7.05 (m, 2H), 6.84 (d, 1H, major rotamer), 6.79 (d,1H, minor rotamer), 6.26 (d, 1H), 4.33 (dd, 1H, major rotamer), 4.04(dd, 1H, minor rotamer), 3.81 (s, 3H), 3.72 (s, 3H, major rotamer), 3.71(s, 3H, minor rotamer), 3.49-3.56 (m, 2H, minor rotamer), 3.23 (t, 2H,major rotamer), 3.10 (s, 3H), 2.12-2.26 (m, 1H), 1.76-1.95 (m, 3H), 1.27(s, 9H).

LCMS (of hydrochloride salt) m/z 797 (M+H)⁺ (ES⁺)

(ax)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxybenzoicacid

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.41 (s, 1H),8.69 (s, 1H), 8.40 (d, 1H), 8.32 (d, 1H), 8.06 (d, 1H), 7.82 (d, 1H),7.67-7.59 (m, 1H), 7.59-7.49 (m, 2H), 7.37 (d, 1H), 7.21-7.05 (m, 2H),7.03 (d, 1H), 6.90 (s, 1H), 6.54 (d, 1H), 3.78 (s, 3H), 2.57 (s, 3H),1.22 (s, 9H). -Me obscured by water peak 3.33 ppm

LCMS (of sodium salt) m/z 701 (M+H)⁺ 723 (M+Na)⁺ (ES⁺)

(ay)3-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propanoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.76 (bs, 1H), 9.55(s, 1H), 9.13 (s, 1H), 8.99 (s, 1H), 8.36 (d, 1H), 8.27 (t, 1H), 8.18(d, 1H), 8.12-8.15 (m, 2H), 7.86 (d, 1H), 7.79 (d, 1H), 7.70-7.74 (m,1H), 7.62-7.65 (m, 1H), 7.43 (d, 1H), 7.40 (s, 1H), 7.11 (d, 1H), 7.03(d, 1H), 6.77 (dd, 1H), 6.25 (d, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.48(q, 2H), 3.10 (s, 3H), 2H under H2O, 1.27 (s, 9H).

LCMS (of hydrochloride salt) m/z 771 (M+H)⁺ (ES⁺)

(az)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.38 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.46 (d, 1H), 8.27 (d, 1H), 8.19 (d, 1H), 8.08 (d, 1H),7.84 (d, 1H), 7.76-7.53 (m, 3H), 7.41 (d, 1H), 7.03 (d, 1H), 6.88 (s,2H), 6.65 (d, 1H), 3.81 (s, 3H), 3.17 (q, 2H), 3.10 (s, 3H), 2.47-2.20(m, 10H), 2.16 (s, 3H), 1.27 (s, 9H). 2×—OMe obscured by water peak.

LCMS m/z 856 (M+H)⁺ (ES⁺)

(ba)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(1-methylpiperidin-4-yl)ethyl)benzenesulfonamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.14 (bs, 1H), 8.90 (s, 1H),8.30 (d, 1H), 8.17-8.10 (m, 3H), 7.86 (d, 1H), 7.70 (dd, 1H), 7.62-7.59(m, 2H), 7.53 (d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H), 7.02 (d, 1H), 6.68(dd, 1H), 6.16 (d, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.07 (s, 3H), 3.01(t, 2H), 2.66-2.64 (m, 5H), 2.08 (s, 3H), 1.73 (t, 2H), 1.56-1.53 (m,2H), 1.32 (q, 2H), 1.26 (s, 9H), 1.12-1.03 (m, 3H).

LCMS m/z 874 (M+H)⁺ (ES⁺)

(bb)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)benzenesulfonamide

¹H NMR (400 MHz, DMSO-d6) 9.39 (bs, 2H), 9.13 (bs, 1H), 8.90 (s, 1H),8.30 (d, 1H), 8.18-8.16 (m, 2H), 8.11 (d, 1H), 7.86 (d, 1H), 7.72-7.69(m, 1H), 7.63-7.59 (m, 2H), 7.54 (d, 1H), 7.40 (d, 1H), 7.23 (dd, 1H),7.02 (d, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 3.80 (s, 3H), 3.79 (s, 3H),3.11 (t, 2H), 3.08 (s, 3H), 2.73 (s, 3H), 2.37 (t, 2H), 2.33-2.25 (m,8H), 2.10 (s, 3H), 1.26 (s, 9H).

LCMS m/z 875.4 (M+H)⁺ (ES⁺)

(bc)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-(dimethylamino)benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.40 (s, 1H), 8.92 (s, 1H),8.50 (d, 1H), 8.30 (d, 1H), 8.15 (d, 1H), 8.12 (d, 1H), 7.85 (d, 1H),7.70-7.66 (m, 2H), 7.63-7.57 (m, 2H), 7.43 (d, 1H), 7.30 (d, 1H), 7.02(d, 1H), 6.74 (d, 1H), 3.81 (s, 3H), 3.08 (s, 3H), 2.42 (s, 6H), 1.26(s, 9H).

LCMS m/z 714 (M+H)⁺ (ES⁺)

(bd)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(5-(dimethylamino)pentyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.24 (s, 1H), 9.13 (bs 1H),8.91 (s, 1H), 8.31 (d, 1H), 8.11-8.18 (m, 3H), 7.94 (t, 1H), 7.87 (d,1H), 7.69-7.73 (m, 2H), 7.59-7.63 (m, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.22 (dd, 1H), 7.03 (d, 1H), 6.65 (dd, 1H), 6.15 (d, 1H), 3.84 (s, 3H),3.81 (s, 3H), 3.25 (q, 2H), 3.09 (s, 3H), 2.17 (t, 2H), 2.10 (s, 6H),1.46-1.54 (m, 2H), 1.37-1.45 (m, 2H), 1.24-1.33 (m, 2H), 1.27 (s, 9H).

LCMS m/z 812 (M+H)⁺ (ES⁺)

(be)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-ethylpiperazin-1-yl)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (bs, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.22 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.60-7.63 (m, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.24(dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.87 (s, 3H), 3.81(s, 3H), 3.37 (q, 2H), 3.10 (s, 3H), 2.29-2.50 (m, 12H), 1.27 (s, 9H),0.99 (t, 3H).

LCMS m/z 839 (M+H)⁺ (ES⁺)

(bf)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-isopropylpiperazin-1-yl)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.23 (m, 4H), 7.87 (d, 1H), 7.78 (d,1H), 7.71 (t, 1H), 7.58-7.63 (m, 2H), 7.40 (d, 1H), 7.23 (d, 1H), 7.03(s, 1H), 6.66 (d, 1H), 6.16 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.37(q, 2H), 3.10 (s, 3H), 2.58-2.64 (m, 2H), 2.34-2.51 (m, 9H), 1.27 (s,9H), 0.97 (d, 6H).

LCMS m/z 853 (M+H)⁺ (ES⁺)

(bg)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.23 (s, 1H), 9.13 (bs, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.21 (t, 1H), 8.11-8.17 (m, 3H), 7.87 (d,1H), 7.69-7.75 (m, 2H), 7.60-7.63 (m, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.21 (dd, 1H), 7.03 (d, 1H), 6.65 (dd, 1H), 6.16 (d, 1H), 4.22 (s, 1H),3.83 (s, 3H), 3.81 (s, 3H), 3.37 (q, 2H), 3.09 (s, 3H), 2.24-2.37 (m,4H), 2.14 (s, 3H), 1.61 (t, 2H), 1.45-1.54 (m, 4H), 1.27 (s, 9H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(bh)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

1:1 mixture of rotamers. ¹H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 9.14(s, 1H), 9.07 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H),8.11-8.13 (m, 2H), 7.87 (d, 1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 1H),7.38-7.40 (m, 2H), 7.19-7.22 (m, 1H), 7.03 (d, 1H), 6.96 (dd, 1H), 6.61(dd, 1H), 6.12 (d, 1H), 3.81 (s, 3H), 3.70 (s, 3H, 1st rotamer), 3.69(s, 3H, 2nd rotamer), 3.48 (t, 1H), 3.10-3.21 (bm, 1H), 3.10 (s, 3H),2.92 (s, 3H, 1st rotamer), 2.76 (s, 3H, 2nd rotamer), 2.15-2.48 (bm,10H), 2.15 (s, 3H, 1st rotamer), 2.08 (s, 3H, 2nd rotamer), 1.27 (s,9H).

LCMS m/z 839 (M+H)⁺ (ES⁺)

(bi)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2,2,4-trimethylpiperazin-1-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 4H), 7.87 (d, 1H), 7.80 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 1H), 7.57 (d, 1H), 7.40 (d, 1H),7.23 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.89 (s, 3H),3.81 (s, 3H), 2H under water, 3.10 (s, 3H), 2.19-2.58 (bm, 6H),2.01-2.16 (m, 2H), 2.12 (s, 3H), 1.27 (s, 9H), 0.97 (s, 6H).

LCMS m/z 853 (M+H)⁺ (ES⁺)

(bj)(S)-2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)-3-hydroxypropanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1H), 9.30 (s, 1H), 8.93 (s, 1H),8.59 (d, 1H), 8.31 (d, 1H), 8.12 (d, 1H), 8.05-8.38 (bm, 3H), 7.87 (d,1H), 7.81 (d, 1H), 7.69-7.73 (m, 1H), 7.60-63 (m, 2H), 7.40 (d, 1H),7.25 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.17 (d, 1H), 4.22-4.30 (m,1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.78-3.81 (m, 1H), 3.58-3.61 (m, 1H),3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 787 (M+H)⁺ (ES⁺)

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.27 (s, 1H),8.82 (d, 1H), 8.69 (s, 1H), 8.33 (d, 1H), 8.17 (d, 1H), 8.11 (d, 1H),7.84 (d, 1H), 7.79 (d, 1H), 7.74-7.63 (m, 2H), 7.63-7.50 (m, 2H), 7.38(d, 1H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.14 (d, 1H), 5.99(s, 1H), 3.95-3.80 (m, 4H), 3.79 (s, 3H), 3.70 (s, 1H), 3.33-3.21 (m,2H), 2.66 (s, 3H), 1.23 (s, 9H).

LCMS (of sodium salt) m/z 787 (M+H)⁺ (ES⁺)

(bk)N-((4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)sulfonyl)propionamide

¹H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.98 (s, 1H), 9.41 (s, 1H),9.13 (s, 1H), 8.92 (s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 8.20 (d, 1H),8.12 (d, 1H), 7.85 (d, 1H), 7.71-7.67 (m, 1H), 7.62-7.58 (m, 1H),7.49-7.41 (m, 3H), 7.15-7.11 (m, 1H), 7.03 (d, 1H), 6.73 (d, 1H), 3.82(s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 2.14 (q, 2H), 1.27 (s, 9H), 0.84(t, 3H).

LCMS m/z 792 (M+H)⁺ (ES⁺); 790 (M−H)⁻ (ES⁻)

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 9.43 (s, 1H),9.17 (s, 1H), 8.84 (s, 1H), 8.44 (d, 1H), 8.28 (d, 1H), 8.19-7.91 (m,2H), 7.84 (dd, 1H), 7.71-7.63 (m, 1H), 7.63-7.52 (m, 1H), 7.41 (d, 1H),7.33 (d, 1H), 7.18 (s, 1H), 7.03 (d, 1H), 6.94 (s, 1H), 6.61 (d, 1H),3.81 (s, 3H), 3.37 (s, 3H), 2.98 (s, 3H), 1.89 (q, 2H), 1.26 (s, 9H),0.84 (t, 3H).

LCMS (of sodium salt) m/z 792 (M+H)⁺ (ES⁺)

(bl)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(1-(4-methylpiperazin-1-yl)propan-2-yl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.25 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.31 (d, 1H), 8.16-8.19 (m, 2H), 8.12 (d, 1H), 7.98 (d,1H), 7.87 (d, 1H), 7.69-7.75 (m, 2H), 7.60-7.63 (m, 1H), 7.58 (d, 1H),7.40 (d, 1H), 7.23 (d, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H),3.97-4.03 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.10 (s, 3H), 2.21-2.43(m, 10H), 2.14 (s, 3H), 1.27 (s, 9H), 1.15 (d, 3H).

LCMS m/z 839 (M+H)⁺ (ES⁺)

(bm)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.16-8.19 (m, 2H), 8.10-8.13 (m, 2H), 7.87(d, 1H), 7.76 (d, 1H), 7.69-7.73 (m, 1H), 7.58-7.64 (m, 2H), 7.40 (d,1H), 7.23 (dd, 1H), 7.02 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.62 (t,1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.51-3.55 (m, 4H), 3.42-3.47 (m, 4H),3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 787 (M+H)⁺ (ES⁺)

(bn)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-hydroxyethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.16-8.19 (m, 2H), 8.08-8.13 (m, 2H), 7.87(d, 1H), 7.77 (d, 1H), 7.69-7.73 (m, 1H), 7.59-7.64 (m, 2H), 7.40 (d,1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.77 (t,1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.50 (q, 2H), 2H under water, 3.10 (s,3H), 1.27 (s, 9H).

LCMS m/z 743 (M+H)⁺ (ES⁺)

(bo)4-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.28 (s, 1H), 9.21 (s, 1H),8.85 (s, 1H), 8.20-8.23 (m, 2H), 8.17 (d, 1H), 8.08 (d, 1H), 7.86 (d,1H), 7.77 (d, 1H), 7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H), 7.57 (d, 1H),7.40 (d, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.24 (dd, 1H), 6.89 (s, 1H),6.67 (dd, 1H), 6.15 (d, 1H), 3.87 (s, 3H), 2H under water, 3.01 (s, 3H),2.22-2.50 (m, 10H), 2.17 (s, 3H), 1.28 (s, 9H).

LCMS m/z 795 (M+H)⁺ (ES⁺)

(bp)4-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(3-(4-methylpiperazin-1-yl)propyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.25 (s, 1H), 9.19 (s, 1H),8.83 (s, 1H), 8.22 (d, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.98 (t, 1H),7.86 (d, 1H), 7.69-7.72 (m, 2H), 7.59-7.63 (m, 1H), 7.55 (d, 1H), 7.40(d, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.22 (dd, 1H), 6.89 (s, 1H), 6.66(dd, 1H), 6.14 (d, 1H), 3.83 (s, 3H), 3.27 (q, 2H), 3.01 (s, 3H),2.19-2.46 (m, 10H), 2.13 (s, 3H), 1.63 (quint, 2H), 1.28 (s, 9H).

LCMS m/z 809 (M+H)⁺ (ES⁺)

(bq)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.49 (t, 1H), 9.40 (s, 1H), 9.10-9.17 (m,2H), 8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.11-8.16 (m, 2H), 7.87(d, 1H), 7.68-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.47 (d, 1H), 7.39-7.43(m, 2H), 7.03 (d, 1H), 6.64 (dd, 1H), 6.14 (d, 1H), 3.81 (s, 3H), 3.38(q, 2H), 3.10 (s, 3H), 2.62 (s, 6H), 2.20-2.48 (m, 10H), 2.15 (s, 3H),1.27 (s, 9H).

LCMS m/z 838 (M+H)⁺ (ES⁺)

(br)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 9.42 (s, 1H), 9.16 (s, 1H),8.94 (s, 1H), 8.31 (d, 1H), 8.13-8.19 (m, 3H), 7.98 (d, 1H), 7.79-7.88(m, 2H), 7.70-7.74 (m, 1H), 7.61-7.65 (m, 1H), 7.55 (s, 1H), 7.42 (d,1H), 7.21 (d, 1H), 7.03 (d, 1H), 6.72 (d, 1H), 6.59 (bs, 1H), 6.19 (s,1H), 5.08 (d, 1H—Major anomer), 4.64 (s, 1H—Minor anomer), 3.87 (s, 3H),3.81 (s, 3H), 3.81-3.87 (m, 1H), 3.60-3.71 (m, 2H), 3.44-3.54 (m, 2H),3.13-3.21 (m, 1H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 861 (M+H)⁺ (ES⁺)

(bs)4-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-methylpiperidin-4-yl)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 9.25 (s, 1H), 9.19 (s, 1H),8.83 (s, 1H), 8.22 (d, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.93 (t, 1H),7.86 (d, 1H), 7.68-7.72 (m, 2H), 7.59-7.63 (m, 1H), 7.55 (d, 1H), 7.40(d, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 7.22 (dd, 1H), 6.88 (s, 1H), 6.66(dd, 1H), 6.14 (d, 1H), 3.83 (s, 3H), 3.28 (q, 2H), 3.01 (s, 3H), 2.71(d, 2H), 2.12 (s, 3H), 1.79 (t, 2H), 1.64 (d, 2H), 1.42 (q, 2H), 1.28(s, 9H), 1.09-1.22 (m, 3H).

LCMS m/z 794 (M+H)⁺ (ES⁺)

(bt)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.44 (t, 1H), 9.39 (s, 1H), 9.16 (s, 1H),9.14 (s, 1H), 8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.11-8.16 (m,2H), 7.87 (d, 1H), 7.67-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.49 (d, 1H),7.39-7.42 (m, 2H), 7.03 (d, 1H), 6.64 (m, 1H), 6.14 (d, 1H), 4.57 (t,1H), 3.81 (s, 3H), 3.41-3.55 (m, 12H), 3.10 (s, 3H), 2.62 (s, 6H), 1.27(s, 9H).

LCMS m/z 844 (M+H)⁺ (ES⁺)

(bu)(S)-2-Amino-6-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoicacid

¹H NMR (of dihydrochloride salt; 400 MHz, DMSO-d6) δ: 10.23 (bs, 1H),9.88 (s, 1H), 9.17 (s, 1H), 9.13 (s, 1H), 8.47 (d, 1H), 8.39-8.40 (m,3H), 8.11-8.16 (m, 3H), 8.07 (t, 1H), 8.07-8.48 (bm, 1H), 7.85 (d, 1H),7.69-7.76 (m, 2H), 7.62-7.66 (m, 1H), 7.45 (d, 1H), 7.28 (s, 1H),7.03-7.05 (m, 2H), 6.82 (dd, 1H), 6.35 (s, 1H), 3.83-3.91 (m, 1H), 3.91(s, 3H), 3.82 (s, 3H), 3.26 (q, 2H), 3.10 (s, 3H), 1.77-1.88 (m, 2H),1.35-1.58 (m, 4H), 1.27 (s, 9H).

LCMS (of dihydrochloride salt) m/z 414 (M+2H)²⁺ (ES⁺)

(bv)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(2-(2-(((3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H),8.91 (s, 1H), 8.31 (d, 1H), 8.07-8.20 (m, 4H), 7.87 (d, 1H), 7.69-7.78(m, 2H), 7.60-7.64 (m, 2H), 7.40 (d, 1H), 7.23 (d, 1H), 7.03 (s, 1H),6.66 (d, 1H), 6.16 (s, 1H), 4.82 (d, 1H), 4.68 (d, 1H), 4.51-4.56 (m,1H), 4.34 (d, 1H), 4.10 (d, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.49-3.62(m, 12H), 3.38-3.46 (m, 2H), 3.20-3.29 (m, 3H), 3.09 (s, 3H), 1.27 (s,9H).

LCMS m/z 993 (M+H)⁺ (ES⁺)

(bw)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.08 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.19 (m, 4H), 7.87 (d, 1H), 7.78 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.64 (m, 2H), 7.40 (d, 1H), 7.23 (dd, 1H),7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.92 (d, 1H), 4.47 (d, 1H),4.40 (t, 2H), 4.33 (t, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.67-3.72 (m,1H), 3.47-3.67 (m, 4H), 3.37-3.45 (m, 2H), 3.17-3.23 (m, 1H), 3.10 (s,3H), 1.27 (s, 9H).

LCMS m/z 863 (M+H)⁺ (ES⁺)

(bx)6-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)hexanoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.96 (s, 1H), 9.65(s, 1H), 9.14 (s, 1H), 9.05 (s, 1H), 8.40 (d, 1H), 8.10-8.17 (m, 3H),8.02 (t, 1H), 7.86 (d, 1H), 7.70-7.75 (m, 2H), 7.62-7.66 (m, 1H), 7.45(d, 1H), 7.32 (s, 1H), 7.06 (d, 1H), 7.03 (d, 1H), 6.81 (d, 1H), 6.29(s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.25 (q, 2H), 3.10 (s, 3H), 2.21(t, 2H), 1.46-1.56 (m, 4H), 1.24-1.34 (m, 11H).

LCMS (of hydrochloride salt) m/z 813 (M+H)⁺ (ES⁺)

(by)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.41 (s, 1H), 9.13 (s, 1H),8.92 (s, 1H), 8.48 (d, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.12 (d, 1H),8.04 (dd, 1H), 7.85 (d, 1H), 7.71-7.67 (d, 1H), 7.62-7.55 (m, 2H), 7.43(d, 1H), 7.36 (s, 1H), 7.10 (br d, 1H), 7.03 (d, 1H), 6.68 (d, 1H), 4.56(t, 1H), 3.82 (s, 3H), 3.60-3.45 (m, 11H), 3.42-3.36 (m, 4H), 3.10 (s,3H), 1.27 (s, 9H).

LCMS m/z 832 (M+H)⁺ (ES⁺); 830 (M−H)⁻ (ES⁻)

(bz)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(1-methylpiperidin-4-yl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (s, br, 1H), 9.01 (s,1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H), 8.11 (d,1H), 7.87 (d, 1H), 7.78-7.66 (m, 2H), 7.66-7.57 (m, 1H), 7.39 (d, 1H),7.03 (d, 1H), 6.92 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H), 3.81 (s, 3H),3.61 (s, 6H), 3.59-3.51 (m, 1H), 3.08 (s, 3H), 2.75-2.61 (m, 2H), 2.13(s, 3H), 1.98-1.83 (m, 2H), 1.77-1.64 (m, 2H), 1.52-1.35 (m, 2H), 1.27(s, 9H).

LCMS m/z 826 (M+H)⁺ (ES⁺)

(ca)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-((1-methylpiperidin-4-yl)methyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H),8.89 (s, 1H), 8.30 (d, 1H), 8.21-8.04 (m, 3H), 7.87 (d, 1H), 7.83 (t,1H), 7.75-7.66 (m, 1H), 7.65-7.57 (m, 1H), 7.39 (d, 1H), 7.03 (d, 1H),6.93 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H), 3.81 (s, 3H), 3.60 (s, 6H),3.06 (s, 3H), 2.98 (t, 2H), 2.79-2.68 (m, 2H), 2.12 (s, 3H), 1.85-1.72(m, 2H), 1.71-1.59 (m, 2H), 1.47-1.32 (m, 1H), 1.27 (s, 9H), 1.19-1.04(m, 2H).

LCMS m/z 840 (M+H)⁺ (ES⁺)

(cb)3-(3-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propoxy)propanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.08-10.01 (bs, 1H), 9.47 (s, 1H), 9.24 (s,1H), 8.96 (s, 1H), 8.31 (d, 1H), 8.16-8.18 (m, 2H), 8.12 (d, 1H), 8.00(t, 1H), 7.87 (d, 1H), 7.69-7.72 (m, 2H), 7.59-7.63 (m, 1H), 7.53 (d,1H), 7.40 (d, 1H), 7.21 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d,1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.59 (t, 2H), 3.43 (t, 2H), 3.30 (q,2H), 3.10 (s, 3H), 2.44 (d, 2H), 1.71 (quint, 2H), 1.27 (s, 9H).

LCMS m/z 829 (M+H)⁺ (ES⁺)

(cc)2-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethyldihydrogen phosphate

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ 9.99 (bs, 1H), 9.30 (s, 1H),9.25 (s, 1H), 8.45 (d, 1H), 8.17 (d, 1H), 8.13-8.08 (m, 3H), 7.83 (dd,1H), 7.74 (d, 1H), 7.65 (dd, 1H), 7.59 (dd, 1H), 7.37 (d, 1H), 7.15 (bs,1H), 7.07 (d, 1H), 7.01 (d, 1H), 6.71 (dd, 1H), 6.17 (d, 1H), 3.86-3.80(m, 5H), 3.56-3.39 (m, 9H), 3.08 (s, 3H), 1.25 (s, 9H).

LCMS (of sodium salt) m/z 867 (M+H)⁺ (ES⁺)

(cd)4-((2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)amino)-4-oxobutanoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.81 (bs, 1H), 9.57(s, 1H), 9.14 (s, 1H), 9.01 (s, 1H), 8.37 (d, 1H), 8.11-8.17 (m, 4H),8.01 (t, 1H), 7.86 (d, 1H), 7.78 (d, 1H), 7.70-7.74 (m, 1H), 7.62-7.66(m, 1H), 7.44 (d, 1H), 7.37 (s, 1H), 7.10 (d, 1H), 7.03 (s, 1H), 6.78(d, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.30-3.37 (m, 2H),3.16-3.25 (m, 2H), 3.10 (s, 3H), 2.44 (t, 2H), 2.33 (t, 2H), 1.27 (s,9H).

LCMS (of hydrochloride salt) m/z 842 (M+H)⁺ (ES⁺)

(ce)3-(3-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)propanamido)propanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 9.28 (s, 1H), 9.08 (s, 1H),8.33 (d, 1H), 8.23 (t, 1H), 8.16-8.18 (m, 2H), 8.12 (d, 1H), 8.02 (t,1H), 7.86 (d, 1H), 7.74 (d, 1H), 7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H),7.45 (s, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.68 (dd, 1H),6.15 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.44 (q, 2H), 3.25 (q, 2H),3.09 (s, 3H), 2.29-2.35 (m, 4H), 1.26 (s, 9H).

LCMS m/z 842 (M+H)⁺ (ES⁺)

(cf)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(3-oxo-3-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)propyl)benzamide

¹H NMR (400 MHz, DMSO-d6, 333K) δ 9.27 (s, 1H), 9.11 (s, 1H), 8.88 (s,1H), 8.75 (s, 1H), 8.29 (d, 1H), 8.24 (t, 1H), 8.16-8.14 (m, 2H), 8.07(d, 1H), 7.90 (dd, 1H), 7.76 (d, 1H), 7.71-7.67 (m, 1H), 7.62-7.58 (m,1H), 7.55 (d, 1H), 7.36 (d, 1H), 7.21 (dd, 1H), 7.05 (d, 1H), 6.61 (dd,1H), 6.22 (d, 1H), 5.00 (bs, 1H), 4.79 (bs, 2H), 4.53 (bs, 1H), 3.84 (s,3H), 3.83 (s, 3H), 3.65-3.49 (m, 7H), 3.09 (s, 3H), 3.68-3.65 (m, 2H),1.28 (s, 9H).

LCMS m/z 916.4 (M+H)⁺ (ES⁺); 914.2 (M−H)⁻ (ES⁻)

(cg)N-(5-(tert-Butyl)-3-(3-(4-((2-((4-(4-(2-(dimethylamino)ethyl)piperazine-1-carbonyl)-3,5-dimethoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide

¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.18 (br, s, 1H), 9.08 (s,1H), 8.93 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.14 (s, 1H), 8.12 (d,1H), 7.86 (d, 1H), 7.76-7.66 (m, 1H), 7.66-7.56 (m, 1H), 7.40 (d, 1H),7.02 (d, 1H), 6.98 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H), 3.81 (s, 3H),3.63 (s, 6H), 3.58-3.47 (br, m, 2H), 3.09 (s, 3H), 3.08-3.04 (br, m,2H), 2.41-2.21 (m, 8H), 2.11 (s, 6H), 1.27 (s, 9H).

LCMS m/z 869 (M+H)⁺ (ES⁺)

(ch)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((3-(4-methylpiperazin-1-yl)propyl)sulfonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.42 (s, 1H), 9.15 (bs, 1H),8.94 (s, 1H), 8.30 (d, 1H), 8.20-8.18 (m, 2H), 8.13 (d, 1H), 7.85 (d,1H), 7.71 (dd, 1H), 7.65-7.55 (m, 3H), 7.41 (d, 1H), 7.30 (d, 1H), 7.01(d, 1H), 6.70 (dd, 1H), 6.17 (d, 1H), 3.84 (s, 3H), 3.80 (s, 3H),3.30-3.26 (m, 2H), 3.09 (s, 3H), 2.34-2.13 (m, 10H), 2.10 (s, 3H), 1.58(quint, 2H), 1.26 (s, 9H).

LCMS m/z 860 (M+H)⁺ (ES⁺); 858 (M−H)⁻ (ES⁻)

(ci)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidine-1-carbonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

Mixture of rotamers. ¹H NMR (400 MHz, DMSO-d6, 100° C.) δ: 9.13 (s, 1H),8.65-8.88 (m, 2H), 8.58 (s, 1H), 8.29 (d, 1H), 8.12 (d, 1H), 8.08 (d,1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.65-7.69 (m, 1H), 7.58-7.62 (m, 1H),7.39 (d, 1H), 7.33 (d, 1H), 7.17 (dd, 1H), 7.09 (d, 1H), 7.02 (d, 1H),6.55 (dd, 1H), 6.29 (d, 1H), 4.83 (bs, 1H), 4.56 (bs, 1H), 4.49 (bs,1H), 3.98-4.28 (m, 2H), 3.86 (s, 3H), 3.53-3.76 (m, 6H), 3.72 (s, 3H),3.32 (d, 1H), 3.07 (s, 3H), 1.30 (s, 9H).

LCMS m/z 845 (M+H)⁺ (ES⁺)

(cj)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.27 (s, 1H), 9.20 (bs, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.21 (t, 1H), 8.16-8.17 (m, 2H), 8.12 (d,1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.6-7.73 (m, 1H), 7.58-7.63 (m, 2H),7.40 (d, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 6.66 (d, 1H), 6.15 (s, 1H),3.87 (s, 3H), 3.81 (s, 3H), 3.55 (bs, 2H), 3.46 (bs, 2H), 3.40 (q, 2H),3.08 (s, 3H), 3.05 (s, 2H), 2.48 (t, 2H), 2.42 (bs, 2H), 2.38 (bs, 2H),2.17 (s, 6H), 1.27 (s, 9H).

LCMS m/z 897 (M+H)⁺ (ES⁺)

(ck)4-(4-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)piperazin-1-yl)-4-oxobutanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.27 (s, 1H), 8.97 (s, 1H),8.32 (d, 1H), 8.21 (t, 1H), 8.11-8.17 (m, 3H), 7.86 (d, 1H), 7.77 (d,1H), 7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H), 7.53 (s, 1H), 7.40 (d, 1H),7.22 (d, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.15 (d, 1H), 3.83 (s, 3H),3.80 (s, 3H), 3.43-3.52 (m, 6H), 2H under water, 3.06 (s, 3H), 2.33-2.47(m, 8H), 1.26 (s, 9H).

LCMS m/z 911 (M+H)⁺ (ES⁺)

(cl)(S)-2-Amino-5-(4-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)piperazin-1-yl)-5-oxopentanoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H),8.32 (d, 1H), 8.11-8.21 (m, 4H), 7.86 (d, 1H), 7.77 (d, 1H), 7.68-7.72(m, 1H), 7.59-7.63 (m, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.29 (bs, 1H),7.22 (d, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 3.83 (s, 3H),3.81 (s, 3H), 8H under water, 3.10 (s, 3H), 2.33-2.55 (m, 7H), 1.82-1.95(m, 2H), 1.27 (s, 9H).

LCMS m/z 940 (M+H)⁺ (ES⁺), 471 (M+2H)²⁺ (ES⁺)

(cm)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.32 (s, 1H), 9.16 (s, 1H),8.92 (s, 1H), 8.58 (s, 1H), 8.31 (d, 1H), 8.17-8.19 (m, 2H), 8.13 (d,1H), 7.81-7.87 (m, 2H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 2H), 7.41 (d,1H), 7.24-7.25 (dd, 1H), 7.03 (d, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 5.05(t, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.58 (d, 6H), 3.09 (s, 3H), 1.27(s, 9H).

LCMS m/z 803 (M+H)⁺ (ES⁺)

(cn)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,2-bis(hydroxymethyl)propyl)-2,6-dimethoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.11 (br, s, 1H), 9.07 (s,1H), 8.91 (s, 1H), 8.31 (d, 1H), 8.23-8.06 (m, 3H), 7.91 (t, 1H), 7.87(d, 1H), 7.75-7.67 (m, 1H), 7.65-7.58 (m, 1H), 7.39 (d, 1H), 7.03 (d,1H), 6.98 (s, 2H), 6.62 (dd, 1H), 6.11 (d, 1H), 4.29 (t, 3H), 3.81 (s,3H), 3.64 (s, 6H), 3.30 (d, 6H), 3.13-2.95 (m, 5H), 1.27 (s, 9H).

LCMS m/z 847 (M+H)⁺ (ES⁺)

(co)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)methyl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.28 (s, 1H), 9.17 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.24 (t, 1H), 8.16-8.18 (m, 2H), 8.12 (d,1H), 7.87 (d, 1H), 7.79 (d, 1H), 7.69-7.73 (m, 1H), 7.59-7.63 (m, 2H),7.40 (d, 1H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H),5.14 (d, 1H), 4.96 (d, 1H), 4.92 (d, 1H), 4.53 (t, 1H), 3.87 (s, 3H),3.81 (s, 3H), 3.67-3.77 (m, 2H), 3.41-3.47 (m, 1H), 3.24-3.30 (m, 1H),3.12-3.20 (m, 3H), 3.08 (s, 3H), 2.97-3.06 (m, 2H), 1.27 (s, 9H).

LCMS m/z 875 (M+H)⁺ (ES⁺)

(cp)2-((5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)-ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)amino)-2-oxoethyldihydrogen phosphate

¹H NMR (of ammonium salt; 400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.27 (s,1H), 8.91 (s, 1H), 8.37-8.30 (m, 1H), 8.20-8.08 (m, 4H), 7.86 (d, 2H),7.73 (dd, 2H), 7.65-7.53 (m, 2H), 7.40 (d, 1H), 7.24 (dd, 1H), 6.67 (dd,1H), 6.14 (d, 1H), 4.37-4.29 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.39(d, 2H), 3.00-2.84 (m, 4H), 2.78-2.68 (m, 4H), 2.60-2.54 (m, 2H), 1.27(s, 9H).

LCMS (of ammonium salt) m/z 904 (M+H)⁺ (ES⁺)

(cq)(R)-4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(1-methylpyrrolidin-3-yl)benzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.26 (s, 1H), 9.16 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.16-8.19 (m, 2H), 8.12 (d, 1H), 7.96 (d,1H), 7.87 (d, 1H), 7.70-7.73 (m, 2H), 7.59-7.63 (m, 2H), 7.40 (d, 1H),7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 4.31-4.39 (m,1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.10 (s, 3H), 2.59-2.67 (m, 2H), 2.41(dd, 1H), 2.31 (q, 1H), 2.25 (s, 3H), 2.41-2.23 (m, 1H), 1.57-1.65 (m,1H), 1.27 (s, 9H).

LCMS m/z 782 (M+H)⁺ (ES⁺)

(cr)(R)-4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-2-methoxybenzamide

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.26 (s, 1H), 9.15 (s, 1H),8.92 (s, 1H), 8.31 (d, 1H), 8.11-8.22 (m, 4H), 7.87 (d, 1H), 7.69-7.77(m, 2H), 7.60-7.63 (m, 1H), 7.56 (s, 1H), 7.40 (d, 1H), 7.23 (d, 1H),7.03 (s, 1H), 6.65-6.66 (m, 1H), 6.15 (s, 1H), 4.70 (s, 1H), 4.21 (s,1H), 3.85 (s, 3H), 3.81 (s, 3H), 2H underwater, 3.10 (s, 3H), 2.71-2.74(m, 1H), 2.63 (q, 1H), 2H under DMSO, 2.42-2.46 (m, 1H), 2.37 (d, 1H),1.96-2.04 (m, 1H), 1.51-1.62 (m, 1H), 1.27 (s, 9H).

LCMS m/z 812 (M+H)⁺ (ES⁺)

(cs)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-chloro-benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.48 (s, 1H), 9.41 (s, 1H), 8.97 (s, 1H),8.31 (d, 1H), 8.23-8.15 (m, 2H), 8.12 (d, 1H), 8.00 (d, 1H), 7.86 (d,1H), 7.76-7.66 (m, 2H), 7.66-7.56 (m, 1H), 7.45 (dd, 1H), 7.41 (d, 1H),7.02 (d, 1H), 6.71 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.10 (s, 3H),1.27 (s, 9H).

LCMS m/z 704/706 (M+H)⁺ (ES⁺)

(ct)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethyl-benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 12.26 (s, 1H), 9.44 (s, 1H), 9.24 (s, 1H),9.16 (s, 1H), 8.95 (s, 1H), 8.31 (d, 1H), 8.11-8.19 (m, 3H), 7.87 (d,1H), 7.69-7.75 (m, 2H), 7.60-7.63 (m, 2H), 7.39-7.43 (m, 2H), 7.03 (s,1H), 6.65 (d, 1H), 6.16 (s, 1H), 3.81 (s, 3H), 3.10 (s, 3H), 2.89 (q,2H), 1.27 (s, 9H), 1.11 (t, 3H).

LCMS m/z 698 (M+H)⁺ (ES⁺)

(cu)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(difluoromethoxy)benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1H), 9.37 (s, 1H), 9.14 (bs, 1H),8.96 (s, 1H), 8.31 (d, 1H), 8.17-8.18 (m, 2H), 8.12 (d, 1H), 7.86 (d,1H), 7.68-7.72 (m, 2H), 7.59-7.65 (m, 2H), 7.47 (d, 1H), 7.40 (d, 1H),7.09 (t, J=76.2 Hz, 1H), 7.03 (d, 1H), 6.68 (dd, 1H), 6.14 (d, 1H), 3.81(s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 736 (M+H)⁺ (ES⁺)

(cv)6-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-4-methoxy-pyridine-3-carboxylicacid

¹H NMR (400 MHz, DMSO-d6) δ: 12.29 (s, 1H), 9.96 (s, 1H), 9.40 (s, 1H),8.93 (s, 1H), 8.42 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.16 (d, 1H),8.11 (d, 1H), 7.88 (d, 1H), 7.75-7.64 (m, 1H), 7.64-7.52 (m, 2H), 7.37(d, 1H), 7.33 (d, 1H), 7.02 (d, 1H), 6.50 (dd, 1H), 3.85 (s, 3H), 3.81(s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 701 (M+H)⁺ (ES⁺)

(cw)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-hydroxy-benzoicacid

¹H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1H), 9.04 (s, 1H), 8.94 (s, 1H),8.30 (d, 1H), 8.19 (d, 1H), 8.14 (d, 1H), 8.11 (d, 1H), 7.87 (dd, 1H),7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 7.30(s, 1H), 7.03 (d, 1H), 6.82 (dd, 1H), 6.62 (dd, 1H), 6.14 (d, 1H), 3.81(s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 686 (M+H)⁺ (ES⁺)

(cx)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-fluoro-benzoicacid

¹H NMR (of hydrochloride salt; 400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 9.45(s, 1H), 9.15 (s, 1H), 8.95 (s, 1H), 8.32 (d, 1H), 8.21 (d, 1H), 8.19(d, 1H), 8.12 (d, 1H), 7.85-7.91 (m, 2H), 7.69-7.75 (m, 2H), 7.60-7.64(m, 1H), 7.42 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.75 (dd, 1H), 6.18(d, 1H), 3.81 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS (of hydrochloride salt) m/z 688 (M+H)⁺ (ES⁺)

(cy)(2S)-2-Amino-3-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]phenyl]-propanoicacid

¹H NMR (of dihydrochloride salt; 400 MHz, DMSO-d6) δ: 9.89 (s, 1H), 9.54(s, 1H), 9.36 (s, 1H), 9.15 (s, 1H), 9.00 (s, 1H), 7.97-8.44 (bm, 2H),8.35 (d, 1H), 8.15-8.21 (m, 2H), 8.12 (d, 1H), 7.87 (d, 1H), 7.60-7.73(m, 6H), 7.41 (d, 1H), 7.29 (d, 1H), 7.22 (d, 2H), 7.03 (s, 1H), 6.68(d, 1H), 6.17 (s, 1H), 4.06-4.14 (m, 1H), 3.91 (s, 3H), 3.81 (s, 3H),3.02-3.14 (m, 2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS (of dihydrochloride salt) m/z 862 (M+H)⁺ (ES⁺)

Example 18

The following compounds are prepared by methods analogous to thosedescribed above.

(a)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-1-methyl-2-morpholino-ethyl]benzamide

(b)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-hydroxy-N-(2-morpholinoethyl)benzamide

(c)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide

(d)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-fluoro-1-piperidyl)ethyl]-2-methoxy-benzamide

(e)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-quinuclidin-4-yl-benzamide

(f)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(quinuclidin-4-ylmethyl)benzamide

(g)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-(2-quinuclidin-4-ylethyl)benzamide

(h)1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-(3-methoxy-4-methylsulfonyl-anilino)-4-pyridyl]oxy]-1-naphthyl]urea

(i)1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-(3-methoxy-4-methylsulfinyl-anilino)-4-pyridyl]oxy]-1-naphthyl]urea

(j)1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-4-(2-morpholinoethylsulfonyl)anilino]-4-pyridyl]oxy]-1-naphthyl]urea

(k)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[3-(1-methyl-4-piperidyl)propyl]benzamide

(l)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[2-(4-piperidyl)ethyl]benzamide

(m)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-N-(4-morpholinobutyl)benzamide

(n)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1R)-1-methyl-3-morpholino-propyl]benzamide

(o)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-N-[(1S)-1-methyl-3-morpholino-propyl]benzamide

(p)2-[5-tert-butyl-2-methoxy-3-[[4-[[2-[3-methoxy-4-[2-(1-oxo-1,4-thiazinan-4-yl)ethylcarbamoyl]anilino]-4-pyridyl]oxy]-1-naphthyl]carbamoylamino]-N-methylsulfonyl-anilino]ethyldihydrogen phosphate

(q)[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphinicacid

(r)[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]phosphonicacid

(s)[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-phenyl]-methyl-phosphinicacid

(t)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzenesulfinicacid

(u)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(trifluoromethoxy)benzoicacid

(v)6-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-pyridine-3-carboxylicacid

(w)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethyl-benzoicacid

Example 192-(2-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethoxy)ethyldihydrogen phosphate

(i) Benzyl(2-(2-(2-((di-tert-butoxyphosphoryl)oxy)ethoxy)ethoxy)ethyl)carbamate

Di-tert-butyl diethylphosphoramidite (1.6 mL, 5.75 mmol) was added to asolution of benzyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.1 g,3.88 mmol) and 5-methyl-1H-tetrazole (700 mg, 8.33 mmol) in THF (10 mL)and the mixture stirred at rt for 3 hours. The reaction mixture wascooled to 0° C. and H₂O₂ (1.6 mL, 15.66 mmol) was added. After 10 min,the cooling bath was removed and the mixture was stirred for a further 3hours. Na₂SO₃ (20 mL of a 10% w/w solution in water) was added and thereaction mixture stirred for 30 min. The resulting mixture waspartitioned between ethyl acetate (25 mL) and water (20 mL). Theorganics were separated, dried over MgSO₄, filtered and concentrated invacuo. The crude product was purified by chromatography on the Companion(40 g column, 0-100% ethyl acetate in iso-hexane) to afford thesub-title compound (1.2 g) as a clear colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.45-7.29 (m, 5H), 5.37 (s, 1H), 5.12 (s, 2H),4.12-4.03 (m, 2H), 3.71 (ddd, 2H), 3.68-3.60 (m, 4H), 3.58 (t, 2H), 3.41(q, 2H), 1.49 (s, 18H).

(ii) 2-(2-(2-Aminoethoxy)ethoxy)ethyl di-tert-butyl phosphate

5% Pd—C, J&M type 39, 50% w/w paste with water (0.3 g) was added to asolution of the product from step (i) above (1.2 g, 2.52 mmol) in EtOH(10 mL) and the mixture stirred under hydrogen (5 bar) for 3 h. Thereaction mixture was filtered (Whatmans GF/F) and the filtrateevaporated to afford the sub-title compound (0.8 g) as a colourless oil.

1H NMR (400 MHz, CDCl₃) δ 4.22-3.98 (m, 2H), 3.79-3.60 (m, 6H),3.60-3.42 (m, 2H), 2.92 (t, 2H), 1.50 (s, 18H).

LCMS m/z 342 (M+H)⁺ (ES⁺); no chromophore

(iii) Di-tert-butyl(2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethoxy)ethyl)-phosphate

HATU (450 mg, 1.183 mmol) was added to a solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 600 mg, 0.815 mmol), theproduct from step (ii) above (380 mg, 1.113 mmol) and Hünig's base (500μL, 2.86 mmol) in DMF (7 mL). The reaction mixture was stirred at rt for16 h. The mixture was poured into water (100 mL) and partitionedrepeatedly with 10% MeOH:DCM (6×100 mL). The organics were separated,bulked, dried (MgSO₄), filtered and evaporated to a brown gum. The crudeproduct was purified by chromatography on silica gel (40 g column, 2%MeOH:DCM to 10%) to afford the sub-title compound (510 mg) as acolourless foam.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.24-8.04 (m, 4H), 7.87 (d, 1H), 7.77 (d,1H), 7.71 (t, 1H), 7.66-7.56 (m, 2H), 7.41 (d, 1H), 7.22 (d, 1H), 7.03(s, 1H), 6.66 (dd, 1H), 6.16 (s, 1H), 3.99-3.89 (m, 2H), 3.86 (s, 3H),3.82 (s, 3H), 3.67-3.47 (m, 8H), 3.47-3.38 (m, 2H), 3.10 (s, 3H), 1.39(s, 18H), 1.27 (s, 9H).

LCMS m/z 967 (M+H-tBu)⁺ (ES⁺)

(iv)2-(2-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethoxy)ethoxy)ethyldihydrogen phosphate

TFA (1 mL, 12.98 mmol) was added to a solution of the product from step(iii) above (510 mg, 0.439 mmol) in DCM (3 mL) and the reaction leftstirring for 16 h. The solvents were evaporated and the residueazeotroped with toluene. The crude product was loaded onto a column ofSCX (10 g) in MeOH. The column was washed with MeOH and then the productwas eluted with 0.7 M ammonia in MeOH. Product-rich fractions wereconcentrated in vacuo to afford the product as the ammonium salt (380mg). [¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 9.45 (s, 1H), 9.09 (s,1H), 8.37 (d, 1H), 8.24-8.03 (m, 4H), 7.85 (d, 1H), 7.75 (d, 1H),7.72-7.64 (m, 1H), 7.63-7.56 (m, 1H), 7.48-7.34 (m, 2H), 7.26 (dd, 1H),7.02 (d, 1H), 6.64 (dd, 1H), 6.20 (d, 1H), 3.82 (s, 3H), 3.80-3.69 (m,4H), 3.53 (s, 3H), 3.52-3.46 (m, 6H), 3.46-3.38 (m, 2H), 3.09 (s, 3H),1.26 (s, 9H); LCMS m/z 911 (M+H)⁺ (ES⁺)]. The ammonium salt (260 mg) wasloaded onto a column of Dowex 50WX2 N⁺ form (20 g) in water (200 μL).The column was washed with water (100 mL) to elute the sodium salt. Theproduct-rich fractions were freeze-dried to afford the sodium salt ofthe title compound (245 mg) as a colourless solid.

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.49 (s, 1H),9.14 (s, 1H), 8.40 (d, 1H), 8.27-8.01 (m, 4H), 7.85 (d, 1H), 7.75 (d,1H), 7.71-7.63 (m, 1H), 7.63-7.53 (m, 1H), 7.48-7.33 (m, 2H), 7.28 (d,1H), 7.03 (d, 1H), 6.63 (dd, 1H), 6.22 (d, 1H), 3.82 (s, 3H), 3.81-3.73(m, 5H), 3.57-3.46 (m, 8H), 3.46-3.37 (m, 2H), 3.09 (s, 3H), 1.27 (s,9H).

LCMS (of sodium salt) m/z 911 (M+H)⁺ (ES⁺)

Example 20N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((3-morpholinopropyl)sulfonyl)phenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

(i) 3-((2-Methoxy-4-nitrophenyl)thio)propan-1-ol

3-Bromopropan-1-ol (352 μL, 3.89 mmol) was added to a solution of2-methoxy-4-nitrobenzenethiol (600 mg, 3.24 mmol) and K₂CO₃ (493 mg,3.56 mmol) in acetone (5 mL). The reaction mixture was stirred at rt for17 hours, concentrated in vacuo, diluted with EtOAc (10 mL) and washedwith 5 wt % aq NaOH (10 mL). The organic layer was dried over MgSO₄,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct was purified by chromatography on the Companion (40 g column,0-100% ethyl acetate in iso-hexane) to afford the sub-title compound(489 mg) as a sticky yellow-brown oil.

LCMS m/z 244 (M+H)⁺ (ES⁺)

(ii) 3-((2-Methoxy-4-nitrophenyl)sulfonyl)propan-1-ol

To a solution of the product from step (i) above (489 mg, 2.010 mmol) inAcOH (2 mL) and H₂O (2 mL) in an ice bath was added H₂O₂ solution (30wt. % in H2O, 616 μL, 6.03 mmol) dropwise. The mixture was then refluxedfor 20 min and cooled. Another aliquot of H₂O₂ solution (30 wt. % inH₂O, 616 μL, 6.03 mmol) was added dropwise in an ice bath. The mixturewas then refluxed for 20 min and cooled. NaHCO₃ was added to neutralisethe solution, followed by ethyl acetate. The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford a yellow solid. The crude product waspurified by chromatography on the Companion (12 g column, 0-100% ethylacetate in iso-hexane) to afford the sub-title compound (259 mg) as ayellow solid.

LCMS m/z 276 (M+H)⁺ (ES⁺)

(iii) 3-((2-Methoxy-4-nitrophenyl)sulfonyl)propyl methanesulfonate

The product from step (ii) above (259 mg, 0.941 mmol) was dissolved inpyridine (1 mL) and treated with methanesulfonyl chloride (95 μL, 1.223mmol) and DMAP (3.45 mg, 0.028 mmol). The reaction mixture was stirredat rt for 1 hour, concentrated to afford an oil that was partitionedbetween DCM (2 mL) and HCl (1 M, 2 mL). The phases were separated via ahydrophobic phase separator, the organic layer was concentrated toafford the sub-title compound (300 mg) as an oil. The product was usedwithout further purification.

(iv) 4-(3-((2-Methoxy-4-nitrophenyl)sulfonyl)propyl)morpholine

To a solution of the crude product from step (iii) above (300 mg) in DMF(5 mL) was added morpholine (148 μL, 1.698 mmol) and K₂CO₃ (106 mg,0.764 mmol). The reaction mixture was stirred at 100° C. for 2 hoursthen over the weekend at rt. Another aliquot of morpholine (148 μL,1.698 mmol) was added. The reaction mixture was stirred at 100° C. for 1hour, then another aliquot of K₂CO₃ (106 mg, 0.764 mmol) was added. Thereaction mixture was stirred at 1000° C. for 1 hour then concentrated invacuo. The crude product was purified by chromatography on the Companion(12 g column, 0-10% MeOH in DCM) to afford a thick yellow oil. Theproduct was diluted in ethyl acetate (5 mL), washed with water (5 mL)then brine (5 mL), dried via a phase separator and concentrated in vacuoto afford the sub-title compound (61 mg) as a thick yellow film.

¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d, 1H), 7.96 (dd, 1H), 7.89 (d, 1H),4.13 (s, 3H), 3.71-3.69 (m, 4H), 3.53-3.49 (m, 2H), 2.46-2.41 (m, 6H),1.96-1.88 (m, 2H).

LCMS m/z 345 (M+H)⁺ (ES⁺)

(v) 3-Methoxy-4-((3-morpholinopropyl)sulfonyl)aniline

A suspension of the product from step (iv) above (60 mg, 0.174 mmol) and5% Pd/C (50% paste with water, 20 mg) in ethanol (2 mL) was stirredunder hydrogen (5 bar) for 2 h at rt. The reaction mixture was filteredthrough Celite, concentrated in vacuo. The residue was suspended inethanol (2 mL) and fresh 5% Pd/C (50% paste with water, 20 mg) wasadded. The reaction mixture was stirred under hydrogen (5 bar) foranother hour at rt. The reaction mixture was filtered through Celite,concentrated in vacuo to afford the sub-title compound (44 mg) as ayellow oil.

LCMS m/z 315 (M+H)⁺ (ES⁺); 313 (M−H)⁻ (ES⁻)

(vi)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((3-morpholinopropyl)sulfonyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A mixture of the product from step (v) above (44 mg, 0.133 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 76 mg, 0.133 mmol), K₂CO₃ (37 mg, 0.268 mmol),and Brett Phos G3 catalyst (3 mg, 3.31 μmol) were degassed under vacuumback-filling with nitrogen 3 times. tBuOH (2 mL) was added and thesuspension degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 24 h. The reaction was cooled and diluted with DCM. The solution wasfiltered through Celite, washed with DCM and concentrated in vacuo. Thecrude product was purified by chromatography on the Companion (4 gcolumn, 1-8% MeOH in DCM) to afford a pale orange oil which was purifiedby preparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford the title compound (23 mg) as a colourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.39 (s, 1H), 9.14 (s, 1H),8.90 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.16 (d, 1H), 8.12 (d, 1H),7.85 (d, 1H), 7.71 (dd, 1H), 7.65 (d, 1H), 7.61 (dd, 1H), 7.56 (d, 1H),7.40 (d, 1H), 7.31 (dd, 1H), 7.02 (d, 1H), 6.70 (dd, 1H), 6.18 (d, 1H),3.84 (s, 3H), 3.80 (s, 3H), 3.50 (t, 4H), 3.07 (s, 3H), 2.25 (t, 2H),2.20-2.18 (m, 4H), 1.61 (quint, 2H), 1.26 (s, 9H). (2H under the watersignal)

LCMS m/z 847 (M+H)⁺ (ES⁺); 424 (M+2H)²⁺ (ES⁺)

Example 214-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yloxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-morpholinoethyl)benzamide

(i) 2-(Dimethylamino)-N-(2-morpholinoethyl)-4-nitrobenzamide

HATU (662 mg, 1.741 mmol) was added to a stirred solution of2-(dimethylamino)-4-nitrobenzoic acid (244 mg, 1.161 mmol),2-morpholinoethanamine (181 mg, 1.393 mmol) and Hünig's base (912 μL,5.22 mmol) in DMF (5 mL) at rt. The mixture was stirred overnight. Thereaction was diluted with water (25 mL) and the aqueous phase extractedwith EtOAc (2×10 mL). The combined organic phase was washed with water(2×5 mL) and reduced to around half its initial volume in vacuo. Theresulting solution was loaded onto a pre-conditioned cartridge of SCXresin. The resin was washed with MeOH then the product release in 1% NH₃in MeOH. The ammonia solution was concentrated in vacuo affording thesub-title compound (292 mg) as a dark orange oil.

¹H NMR (400 MHz, DMSO-d6) δ: 8.71 (t, 1H), 7.69-7.71 (m, 2H), 7.59-7.61(m, 1H), 3.57-3.59 (m, 4H), 3.39 (q, 2H), 3.34 (s, 6H), 2.47 (t, 2H),2.41 (bs, 4H).

(ii) 4-Amino-2-(dimethylamino)-N-(2-morpholinoethyl)benzamide

5% Pd/C (50% paste with water, 200 mg) was added to a degassed solutionof the product from step (i) above (292 mg, 0.906 mmol) in MeOH (10 mL).The reaction was degassed with H₂ and stirred under a H₂ atmosphere for2 h. The reaction mixture was degassed with N₂ then filtered throughcelite and the filtrate concentrated in vacuo affording the sub-titlecompound (250 mg) as a colourless oil which solidified on standing.

LCMS m/z 293 (M+H)⁺ (ES⁺)

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)-N-(2-morpholinoethyl)benzamide

A suspension of the product from step (ii) above (100 mg, 0.342 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 195 mg, 0.342 mmol), K₂CO₃ (120 mg, 0.868mmol), and BrettPhos G1 precatalyst (10 mg, 0.013 mmol) in DMF (4 mL)was degassed with nitrogen for 10 mins. The reaction was then heatedunder nitrogen at 85° C. (block temperature) for 2 h. The reaction wascooled and partitioned between EtOAc (20 mL) and water (20 mL). Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuoaffording a dark yellow oil. The crude product was purified bypreparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford a beige solid. The crude product was re-purified bypreparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, WatersX-Select Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) toafford a white solid. The solid was partitioned between 10% MeOH in DCMand sat. aq. NaHCO₃ solution. The organic phase was dried viahydrophobic frit and concentrated in vacuo then re-concentrated fromMeCN to afford the title compound (103 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.48 (t, 1H), 9.39 (s, 1H), 9.14-9.16 (m,2H), 8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.11-8.16 (m, 2H), 7.87(d, 1H), 7.68-7.73 (m, 2H), 7.60-7.63 (m, 1H), 7.48 (d, 1H), 7.39-7.42(m, 2H), 7.03 (d, 1H), 6.64 (dd, 1H), 6.14 (d, 1H), 3.81 (s, 3H),3.58-3.60 (m, 4H), 3.39 (q, 2H), 310 (s, 3H), 2.63 (s, 6H), 2.46 (t,2H), 2.41 (bs, 4H), 1.27 (s, 9H).

LCMS m/z 825 (M+H)⁺ (ES⁺); 413 (M+2H)²⁺ (ES⁺)

Example 224-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

(i) Sodium 4-amino-2,6-dimethoxybenzoate

NaOH solution 50% w/w (4 mL, 76 mmol) was added to a solution of methyl4-amino-2,6-dimethoxybenzoate (2 g, 9.47 mmol) in MeOH (40 mL). Thereaction was heated at 60° C. (block temperature) for 16 h. The reactionmixture was cooled in an ice bath filtered and washed with ice coldmethanol (1 mL) then dried to constant weight to afford the sub-titlecompound (1.75 g) as a tan crystalline solid.

LCMS m/z 198 (M+H)⁺ (ES⁺)

(ii) 4-((tert-Butoxycarbonyl)amino)-2,6-dimethoxybenzoic acid

TEA (900 μL, 6.46 mmol) was added to a solution of the product from step(i) above (0.68 g, 3.09 mmol) in 1,4-dioxane (7 mL) and water (3 mL).The mixture was stirred for 5 minutes then di-tert-butyl dicarbonate(1.4 g, 6.41 mmol) was added in one portion and the reaction mixtureleft stirring for 16 h. The organics were evaporated and the aqueousresidue acidified to pH 1 with 1N HCl. The resulting solid was filteredoff, washed with water (5 mL), isohexane (5 mL) and dried to constantweight to afford the sub-title compound (550 mg) as a tan solid.

¹H NMR (400 MHz, CDCl₃) δ 6.74 (s, 2H), 6.66 (s, 1H), 3.91 (s, 6H), 1.53(s, 9H).

(iii) tert-Butyl(3,5-dimethoxy-4-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)phenyl)carbamate

HATU (700 mg, 1.841 mmol) was added to a solution of the product fromstep (ii) above (400 mg, 1.345 mmol),2-(4-methylpiperazin-1-yl)ethanamine (300 mg, 2.095 mmol) and Hünig'sbase (700 μL, 4.01 mmol) in DCM (5 mL). The reaction mixture was stirredat rt for 16 h. The mixture was partitioned between DCM (15 mL) andwater (15 mL). The organics were separated, dried (MgSO₄) filtered andevaporated to give a yellow gum which was pre-absorbed onto silica (4 g)and purified by chromatography on silica gel (12 g column, 2% MeOH:DCMto 10%) to afford the sub-title compound (410 mg) as a pale yellowglass.

¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.72 (t, 1H), 6.83 (s, 2H),3.66 (s, 6H), 3.28-3.15 (m, 2H), 2.48-2.25 (m, 10H), 2.17 (s, 3H), 1.48(s, 9H).

LCMS m/z 423 (M+H)⁺ (ES⁺)

(iv) 4-Amino-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

TFA (2 mL, 26.0 mmol) was added to a solution of the product from step(iii) above (400 mg, 0.947 mmol) in DCM (10 mL) and the reaction stirredovernight. The solvents were evaporated and the residue was loaded ontoa column of SCX (10 g) in MeOH. The column was washed with MeOH and thenthe product was eluted with 0.7 M ammonia in MeOH. The filtrate wasconcentrated in vacuo to afford the sub-title compound (295 mg) as apale yellow crystalline solid.

LCMS m/z 323 (M+H)⁺ (ES⁺)

(v)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 150 mg, 0.264 mmol), the product from step (iv)above (120 mg, 0.372 mmol), K₂CO₃ (100 mg, 0.724 mmol), and BrettPhos G1Precatalyst (5 mg, 5.64 μmol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (2 mL) was added and the stirred suspensionwas degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 1 h. The mixture was cooled to rt and partitioned between water (25mL) and 10% MeOH:DCM (2×20 mL). The organics were bulked and washed with20% w/w NaCl solution, separated, dried (MgSO₄), filtered and thesolvent evaporated to a dark oil. The crude product was purified bypreparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford the title compound (115 mg) as a colourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (s, br, 1H), 9.02 (s,1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.15-8.05 (m, 2H), 7.87(dt, 1H), 7.78-7.54 (m, 3H), 7.39 (d, 1H), 7.03 (d, 1H), 6.93 (s, 2H),6.61 (dd, 1H), 6.11 (d, 1H), 3.81 (s, 3H), 3.61 (s, 6H), 3.21 (q, 2H),3.10 (s, 3H), 2.48-2.17 (m, 10H), 2.14 (s, 3H), 1.27 (s, 9H).

LCMS m/z 855 (M+H)⁺ (ES⁺)

Example 234-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(3-morpholinopropyl)benzamide

(i) tert-Butyl(3,5-dimethoxy-4-((3-morpholinopropyl)carbamoyl)phenyl)carbamate

HATU (350 mg, 0.920 mmol) was added to a solution of4-((tert-butoxycarbonyl)amino)-2,6-dimethoxybenzoic acid (see Example22(ii) above; 200 mg, 0.673 mmol), 3-morpholinopropan-1-amine (152 μL,1.040 mmol) and Hünig's base (350 μL, 2.004 mmol) in DCM (2 mL). Thereaction mixture was stirred at rt for 16 h. The mixture was partitionedbetween DCM (15 mL) and water (15 mL). The organics were separated,dried (MgSO₄), filtered and evaporated to give a yellow gum which waspurified by chromatography on silica gel (12 g column, 2% MeOH:DCM to10%) to afford the sub-title compound (275 mg) as a pale yellow glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.68-7.49 (m, 1H), 6.85 (s,2H), 3.67 (s, 6H), 3.63-3.46 (m, br, 2H), 3.26-3.09 (m, br, 4H), 2.90(s, 4H), 2.47-2.18 (m, br, 2H), 1.87-1.59 (m, br, 2H), 1.48 (s, 9H).

LCMS m/z 424 (M+H)⁺ (ES⁺)

(ii) 4-Amino-2,6-dimethoxy-N-(3-morpholinopropyl)benzamide

TFA (1 mL, 12.98 mmol) was added to a solution of the product from step(i) above (295 mg, 0.697 mmol) in DCM (5 mL) and the reaction stirredovernight. The solvents were evaporated and the residue was loaded ontoa column of SCX (5 g) in MeOH. The column was washed with MeOH and thenthe product was eluted with 0.7 M ammonia in MeOH. The resultant mixturewas concentrated in vacuo to afford the sub-title compound (190 mg) as apale yellow solid.

LCMS m/z 324 (M+H)⁺ (ES⁺)

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxy-N-(3-morpholinopropyl)benzamide

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 140 mg, 0.246 mmol), the product from step (ii)above (100 mg, 0.309 mmol), K₂CO₃ (150 mg, 1.085 mmol), and BrettPhos G1Precatalyst (5 mg, 5.64 μmol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (2 mL) was added and the stirred suspensionwas degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 1 h. The mixture was cooled to rt and partitioned between water (25mL) and 10% MeOH:DCM (2×50 mL). The organics were bulked and washed with20% w/w NaCl solution, separated, dried (MgSO₄), filtered and thesolvent evaporated to a dark oil. The crude product was purified bypreparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford the title compound (90 mg) as a colourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.13 (d, 1H), 8.12 (d, 1H),7.87 (d, 1H), 7.82 (t, 1H), 7.75-7.68 (m, 1H), 7.65-7.58 (m, 1H), 7.39(d, 1H), 7.03 (d, 1H), 6.93 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H), 3.81(s, 3H), 3.61 (s, 6H), 3.54 (t, 4H), 3.14 (q, 2H), 3.10 (s, 3H),2.46-2.21 (m, 6H), 1.58 (p, 2H), 1.27 (s, 9H).

LCMS m/z 856 (M+H)⁺ (ES⁺)

Example 24N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2H-tetrazol-5-yl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

(i) tert-Butyl(4-((2-((4-cyano-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

tert-Butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (seeExample 1(i) above; 2.5 g, 6.74 mmol), 4-amino-2-methoxybenzonitrile (1g, 6.75 mmol), BrettPhos G1 precatalyst (100 mg, 0.125 mmol), NaOtBu(1.3 g, 13.53 mmol) were degassed for 3 min. The tBuOH (20 mL) wasadded, and the mixture was degassed for 3 min. The reaction mixture wasstirred at 75° C. for 2 h and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel (80 g column, 0-5%MeOH/DCM) then purified further by chromatography on silica gel (80 gcolumn, 0-50% EtOAc/isohexane) to afford the sub-title compound (1.087g) as a foam

¹H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.41 (s, 1H), 8.20 (d, 1H),8.14 (d, 1H), 7.82 (d, 1H), 7.65-7.55 (m, 4H), 7.49 (d, 1H), 7.38 (d,1H), 7.26 (dd, 1H), 6.73 (dd, 1H), 6.14 (d, 1H), 3.82 (s, 3H), 1.53 (s,9H).

LCMS m/z 483 (M+H)⁺ (ES⁺); 481 (M−H)⁻ (ES⁻)

(ii) tert-Butyl(4-((2-((3-methoxy-4-(2H-tetrazol-5-yl)phenyl)amino)pyridin-4-yl)oxy)-naphthalen-1-yl)carbamate

A mixture of the product from step (i) above (500 mg, 1.036 mmol) andazidotributylstannane (1.2 g, 3.61 mmol) in glyme (10 mL) were heatedunder reflux for 5 days (solvent evaporated off over the weekend). Theresidue was purified by chromatography on silica gel (80 g column,0-100% EtOAc/isohexane) to afford the sub-title compound (344 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 15.59 (brs, 1H), 9.40 (s, 1H), 9.39 (s, 1H),8.20 (d, 1H), 8.15 (d, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 7.73 (d, 1H),7.66-7.56 (m, 3H), 7.38 (d, 1H), 7.32 (dd, 1H), 6.68 (dd, 1H), 6.15 (d,1H), 3.90 (s, 3H), 1.53 (s, 9H).

LCMS m/z 526 (M+H)+ (ES+); 524 (M−H)− (ES−)

(iii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-methoxy-4-(2H-tetrazol-5-yl)phenyl)pyridin-2-amine

TFA (1 mL, 12.98 mmol) was added to a solution of the product from step(ii) above (339 mg, 0.645 mmol) in DCM (5 mL) and stirred at rt for 5 h.The mixture was evaporated under reduced pressure and the crude productwas loaded onto a column of SCX in MeOH. The column was washed with MeOHand then the product was eluted with 0.7 M ammonia in MeOH. Theresultant mixture was concentrated in vacuo and the residue purified bychromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (196 mg) as brown solid.

¹H NMR (400 MHz, DMSO-d6) δ 15.58 (brs, 1H), 9.30 (s, 1H), 8.19-8.16 (m,1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.70 (d, 1H), 7.66-7.62 (m, 1H),7.48-7.44 (m, 2H), 7.31 (dd, 1H), 7.12 (d, 1H), 6.73 (d, 1H), 6.62 (dd,1H), 6.12 (d, 1H), 5.84 (s, 2H), 3.89 (s, 3H).

LCMS m/z 426 (M+H)⁺ (ES⁺); 424 (M−H)⁻ (ES⁻)

(iv)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2H-tetrazol-5-yl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A mixture of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 210 mg, 0.536 mmol), the product from step (iii)above (190 mg, 0.447 mmol) and Et₃N (81 μL, 0.581 mmol) in THF (3 mL)was heated at 60° C. for 24 h. The mixture was evaporated under reducedpressure and the residue triturated with MeOH. The solid was filteredoff (symmetrical urea) and the filtrate loaded onto a column of SCX. Thecolumn was washed with MeOH and then the product was eluted with 0.7 Mammonia in MeOH. The resultant mixture was concentrated in vacuo and theresidue purified by chromatography on silica gel (40 g column, 0-10%MeOH/DCM) then purified by preparative HPLC (Varian, Basic (0.1%Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 m, 19×50 mmcolumn, 20-50% MeCN in Water) to afford the title compound (104 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 15.59 (s, 1H), 9.40 (s, 1H), 9.37 (s, 1H),9.14 (s, 1H), 8.92 (s, 1H), 8.31 (d, 1H), 8.20-8.19 (m, 2H), 8.13 (d,1H), 7.88 (d, 1H), 7.74-7.70 (m, 2H), 7.64-7.60 (m, 1H), 7.41 (d, 1H),7.33 (dd, 1H), 7.03 (d, 1H), 6.68 (dd, 1H), 6.18 (d, 1H), 3.90 (s, 3H),3.82 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 724 (M+H)⁺ (ES⁺); 722 (M−H)⁻ (ES⁻)

Example 254-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)benzenesulfonamide

(i)2-Methoxy-N-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)-4-nitrobenzenesulfonamide

2-Methoxy-4-nitrobenzene-1-sulfonyl chloride (250 mg, 0.993 mmol) inMeCN (3 mL) was added dropwise to an ice-cold solution ofN-methyl-3-(4-methylpiperazin-1-yl)propan-1-amine (170 mg, 0.993 mmol)and Et₃N (415 μL, 2.98 mmol) in MeCN (3 mL). The reaction mixture wasallowed to warm to rt and stirred for one hour. The reaction wasconcentrated in vacuo, the residue diluted with EtOAc (5 mL), filteredand concentrated in vacuo to give a brown yellow oil. The crude productwas purified by chromatography on the Companion (12 g column, 0-10% MeOHin DCM) to afford the sub-title compound (227 mg) as a sticky yellowoil.

LCMS m/z 387 (M+H)⁺ (ES⁺)

(ii)4-Amino-2-methoxy-N-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)benzenesulfonamide

A suspension of the product from step (i) above (227 mg, 0.587 mmol) and5% Pd/C (50% paste with water, 150 mg) in ethanol (5 mL) was stirredunder hydrogen (5 bar) for 2 h. The reaction mixture was filteredthrough celite, washed with methanol and concentrated in vacuo to affordthe sub-title compound (162 mg) as a pale yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.33 (d, 1H), 6.24 (d, 1H), 6.13 (dd, 1H),5.96 (s, 2H), 3.74 (s, 3H), 2.97 (t, 2H), 2.66 (s, 3H), 2.28-2.18 (m,10H), 2.12 (s, 3H), 1.54 (quint., 2H).

LCMS m/z 357 (M+H)⁺ (ES⁺); 355 (M−H)⁻ (ES⁻)

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-methyl-N-(3-(4-methylpiperazin-1-yl)propyl)benzenesulfonamide

A suspension of the product from step (ii) above (68 mg, 0.179 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 102 mg, 0.179 mmol), K₂CO₃ (74 mg, 0.535 mmol),and BrettPhos G3 precatalyst (5 mg, 5.52 μmol) in DMF (7 mL) wasdegassed with nitrogen for 10 mins. The reaction was then heated undernitrogen at 85° C. (block temperature) for 2 h, cooled to rt and addedto water (20 mL). The organic layer was extracted with DCM (20 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by chromatography on the Companion (4 g column, 0-20% MeOHin DCM) then purified by preparative HPLC (Varian, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,20-50% MeCN in Water) to afford the title compound (6 mg) as acolourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.14 (bs, 1H), 8.88 (s, 1H),8.30 (d, 1H), 8.18 (d, 1H), 8.12-8.10 (m, 2H), 7.85 (d, 1H), 7.68 (dd,1H), 7.59-7.52 (m, 3H), 7.39 (d, 1H), 7.24 (dd, 1H), 7.02 (d, 1H), 6.68(dd, 1H), 6.16 (d, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.04 (s, 3H), 3.00(t, 2H), 2.69 (s, 3H), 2.25 (bs, 6H), 2.17 (t, 2H), 2.10 (s, 3H), 1.54(quint, 2H), 1.26 (s, 9H).

LCMS m/z 889 (M+H)⁺ (ES⁺)

Example 264-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-cyclopropylpiperazin-1-yl)ethyl)-2-methoxybenzamide

HATU (80 mg, 0.210 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 100 mg, 0.136 mmol),2-(4-cyclopropylpiperazin-1-yl)ethanamine (33 mg, 0.166 mmol) andHünig's base (100 μL, 0.573 mmol) in DMF (2 mL) at rt. The mixture wasstirred overnight then poured into water (10 mL) and partitioned withEtOAc (10 mL). The organic phase was concentrated in vacuo. The residuewas dissolved in DMSO (2 mL) and transferred to a 96 well plate. Thecrude product was purified by preparative HPLC (Waters, Acidic (0.1%Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column,20-50% MeCN in Water) to afford a pale yellow solid. The solid waspartitioned between NaHCO₃ solution and 10% MeOH in DCM. The organicphase was dried via hydrophobic frit and concentrated in vacuo. Theresidue was re-concentrated from MeCN and the residue dried in vacuo at45° C. to afford the title compound (48 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 9.13 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.11-8.22 (m, 4H), 7.87 (d, 1H), 7.78 (d,1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 1H), 7.58 (d, 1H), 7.40 (d, 1H),7.24 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.89 (s, 3H),3.81 (s, 3H), 3.36 (q, 2H), 3.10 (s, 3H), 2.55-2.64 (m, 4H), 2.30-2.45(m, 6H), 1.58-1.63 (m, 1H), 1.27 (s, 9H), 0.38-0.42 (m, 2H), 0.27-0.30(m, 2H).

LCMS m/z 851 (M+H)⁺ (ES⁺)

Example 274-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(piperidin-4-yl)ethyl)benzamide

(i) tert-Butyl4-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)piperidine-1-carboxylate

HATU (120 mg, 0.316 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 150 mg, 0.204 mmol),tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (60 mg, 0.263 mmol)and Hünig's base (150 μL, 0.859 mmol) in DMF (2 mL) at rt. The mixturewas stirred overnight then poured into water (10 mL) resulting in theprecipitation of a white solid. The solid was isolated by filtration,washing with additional water, then the solid dried at 50° C. in vacuo.The crude product was purified by chromatography on the Companion (12 gcolumn, 1-5% MeOH in DCM) to afford the sub-title compound (135 mg) as awhite solid.

LCMS m/z 910 (M+H)⁺ (ES⁺)

(ii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(piperidin-4-yl)ethyl)benzamide

TFA (229 μL, 2.97 mmol) was added to a solution of the product from step(i) above (135 mg, 0.148 mmol) in DCM (2 mL) and the reaction leftstirring overnight. The reaction was concentrated in vacuo affording apale yellow oil. The oil was dissolved in DCM and partitioned withNaHCO₃ solution resulting in a gelatinous precipitate. The aqueous phasewas decanted off and the organic phase washed with water. The organicphase was diluted with MeOH affording a homogeneous mixture which wasconcentrated in vacuo affording a white solid. The solid was dissolvedin DMSO (2 mL) and transferred to a 96 well plate. The crude product waspurified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate),Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN inWater) to afford the title compound (68 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.24 (s, 1H), 8.90 (s, 1H),8.31 (d, 1H), 8.11-8.17 (m, 3H), 7.92 (t, 1H), 7.87 (d, 1H), 7.68-7.73(m, 2H), 7.59-7.63 (m, 1H), 7.55 (d, 1H), 7.40 (d, 1H), 7.22 (dd, 1H),7.03 (d, 1H), 6.66 (dd, 1H), 6.15 (d, 1H), 3.83 (s, 3H), 3.81 (s, 3H),3.29 (q, 2H), 3.06 (s, 3H), 2.97 (d, 2H), 2H under DMSO, 1.65 (d, 2H),1.35-1.48 (m, 3H), 1.27 (s, 9H), 1.01-1.11 (m, 2H).

LCMS m/z 810 (M+H)⁺ (ES⁺)

Example 284-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxybenzenesulfonamide

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see, for example, Baker, T. et al., WO 2014/162126, 9 Oct. 2014; 200mg, 0.351 mmol), 4-amino-2-methoxybenzene sulfonamide (120 mg, 0.593mmol) and pTsOH monohydrate (22 mg, 0.116 mmol) in dioxane (2 mL) washeated at 65° C. for 1 h. DMF (0.5 mL) was added and the mixture heatedfor a further 24 h. The mixture was partitioned between EtOAc (40 mL)and sat aq NaHCO₃ (20 mL), the organic layer separated, washed withbrine (20 mL), dried (MgSO₄) and evaporated under reduced pressure. Thecrude product was purified by chromatography on silica gel (40 g column,0-60% MeOH/DCM) to afford the product (180 mg, 95% purity) as a solid.Of that product, 75 mg was purified by preparative HPLC (Varian, Basic(0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm,19×50 mm column, 20-50% MeCN in Water) to afford the title compound (31mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.41 (s, 1H), 9.14 (s, 1H),8.93 (s, 1H), 8.50 (d, 1H), 8.31 (d, 1H), 8.18 (d, 1H), 8.13 (d, 1H),7.85 (d, 1H), 7.71-7.67 (m, 1H), 7.62-7.58 (m, 1H), 7.43 (d, 1H), 7.37(s, 1H), 7.34 (d, 1H), 7.07 (brd, 1H), 7.03 (d, 1H), 6.78 (s, 2H), 6.70(d, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 736 (M+H)⁺ (ES⁺)

Example 294-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-hydroxy-N-(3-morpholinopropyl)benzamide

(i) Methyl2-(benzyloxy)-4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)benzoate

A mixture of methyl 4-amino-2-(benzyloxy)benzoate (149 mg, 0.580 mmol;Azzarito, V. et al., Org. Biomol. Chem. 2012, 10, 6469-6472),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide (see Example 8(i) above; 300 mg, 0.527 mmol), K₂CO₃ (182 mg,1.318 mmol), and Brett Phos G3 catalyst (25 mg, 0.028 mmol) in DMF (6mL) were degassed under nitrogen for 5 min. The reaction was then heatedat 85° C. (block temperature) for 4 h. The mixture was cooled thenpartitioned between EtOAc (50 mL) and water (50 mL). The organic layerwas washed with water (50 mL), dried (MgSO₄), filtered and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel (40 g column, 0-80% EtOAc/isohexane) to afford the sub-titlecompound (342 mg) as a foam.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.33 (s, 1H), 9.14 (s, 1H),8.91 (s, 1H), 8.30 (d, 1H), 8.20-8.18 (m, 2H), 8.12 (d, 1H), 7.87 (d,1H), 7.78-7.60 (m, 4H), 7.52 (d, 2H), 7.41-7.37 (m, 3H), 7.33-7.29 (m,1H), 7.19 (dd, 1H), 7.03 (d, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 5.13 (s,2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

(ii)2-(Benzyloxy)-4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)benzoicacid, hydrochloride salt

Aqueous 1 M NaOH (1.5 mL, 1.500 mmol) was added to a solution of theproduct from step (i) above (335 mg, 0.424 mmol) in THF (4 mL) and MeOH(2 mL) and stirred for 48 h. The solvent was evaporated, the residuedissolved in water (5 mL) then acidified to pH 1 with aqueous 1 M HCl(10 mL). The precipitate was filtered, washed with water then ether anddried under vacuum to afford the sub-title compound (288 mg) as an offwhite solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.67 (s, 1H), 9.13 (s, 1H),9.05 (s, 1H), 8.39 (d, 1H), 8.17 (s, 1H), 8.13 (d, 2H), 7.86 (d, 1H),7.73-7.61 (m, 3H), 7.52-7.29 (m, 7H), 7.06 (d, 1H), 7.03 (s, 1H), 6.78(d, 1H), 6.28 (s, 1H), 5.14 (s, 2H), 3.82 (s, 3H), 3.10 (s, 3H), 1.27(s, 9H).

LCMS m/z 776 (M+H)⁺ (ES⁺)

(iii)2-(Benzyloxy)-4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(3-morpholinopropyl)benzamide

HATU (103 mg, 0.272 mmol) was added to a mixture of the product fromstep (ii) above (184 mg, 0.227 mmol), Hünig's base (100 μL, 0.573 mmol)and 3-morpholinopropan-1-amine (40 mg, 0.277 mmol) in DMF (3 mL) andstirred for 6 h. The mixture was partitioned between EtOAc (30 mL) andwater (20 mL), the organic layer separated, washed with sat aq NaHCO₃soln (20 mL), dried (MgSO₄), filtered and evaporated under reducedpressure. The residue was purified by chromatography on silica gel (24 gcolumn, 0-8% MeOH/DCM) to afford the sub-title compound (154 mg) as afoam.

LCMS m/z 902 (M+H)⁺ (ES⁺); 900 (M−H)⁻ (ES⁻)

(iv)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-hydroxy-N-(3-morpholinopropyl)benzamide

A mixture of the product from step (iii) above (152 mg, 0.169 mmol) and5% Pd/C (30 mg) in EtOH (2 mL) and THF (3 mL) was hydrogenated under aballoon of hydrogen for 24 h then filtered through Celite. The solventwas evaporated and the residue triturated with ether, filtered and driedto afford a solid that was loaded onto a column of SCX in MeOH. Thecolumn was washed with MeOH and then the product was eluted with 0.7 Mammonia in MeOH. The resultant mixture was concentrated in vacuo and theproduct was purified by chromatography on silica gel (24 g column, 0-10%MeOH/DCM) to afford the title compound (77 mg) as a white foam.

¹H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.39 (s, 1H), 9.17 (s, 1H),9.13 (s, 1H), 8.91 (s, 1H), 8.53 (brs, 1H), 8.30 (d, 1H), 8.18 (d, 1H),8.16 (d, 1H), 8.12 (d, 1H), 7.87 (d, 1H), 7.73-7.69 (m, 1H), 7.64-7.59(m, 2H), 7.45 (d, 1H), 7.40 (d, 1H), 7.02 (d, 1H), 6.92 (dd, 1H), 6.66(dd, 1H), 6.14 (d, 1H), 3.81 (s, 3H), 3.57-3.55 (m, 4H), 3.30-3.26 (m,2H), 3.10 (s, 3H), 2.35-2.30 (m, 6H), 1.71-1.64 (m, 2H), 1.27 (s, 9H).

LCMS m/z 812 (M+H)⁺ (ES⁺); 810 (M−H)⁻ (ES⁻)

Example 304-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid

(i) Methyl4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate

Triethylamine (25 μL, 0.179 mmol) was added to a solution of phenyl(3-(tert-butyl)-5-(methylsulfonamido)phenyl)carbamate (see, for example,Baker, T. et al., WO 2014/162126, 9 Oct. 2014; 319 mg, 0.880 mmol) andmethyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate(see Example 1(iii) above; 332 mg, 0.800 mmol) in iPrOAc (15 mL) at 65°C. (block temperature) and the mixture stirred for 24 h. Additionaltriethylamine (25 μL, 0.179 mmol) was added and the temperatureincreased to 75° C. and stirring continued overnight. The reaction wascooled to rt and concentrated in vacuo onto silica gel. The crudeproduct was purified by chromatography on the Companion (40 g column,1-5% MeOH in DCM) to afford the sub-title compound (332 mg) as a palepink gummy solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 9.34 (s, 1H), 9.14 (s, 1H),8.79 (s, 1H), 8.22 (d, 1H), 8.18 (d, 1H), 8.08 (d, 1H), 7.86 (d, 1H),7.69-7.72 (m, 1H), 7.59-7.63 (m, 2H), 7.53 (d, 1H), 7.40 (d, 1H), 7.36(s, 1H), 7.29 (t, 1H), 7.23 (dd, 1H), 6.89 (t, 1H), 6.69 (dd, 1H), 6.17(d, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.01 (s, 3H), 1.28 (s, 9H).

LCMS m/z 684 (M+H)⁺ (ES⁺)

(ii) 4-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)-pyridin-2-yl)amino)-2-methoxybenzoic acid

To a stirred solution of the product from step (i) above (332 mg, 0.486mmol) in THF (15 mL) was added NaOH (2 M aq.) (5.0 mL, 10.00 mmol). MeOH(5 mL) was added and stirring continued overnight. The reaction wasconcentrated in vacuo affording a pale pink solid. The material wasacidified with 1M HCl causing a white solid to precipitate. The solidwas collected by filtration, washing with water. The resulting solid wasdried at 40° C. under vacuum affording4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride (314 mg) as a white solid.

LCMS m/z 670 (M+H)⁺ (ES⁺)

100 mg of the hydrochloride salt was purified by preparative HPLC(Varian, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) to afford thetitle compound (36 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 10.50 (bs, 1H), 9.33 (s, 1H), 9.28 (s, 1H),8.98 (s, 1H), 8.24 (d, 1H), 8.17 (d, 1H), 8.07 (d, 1H), 7.86 (d, 1H),7.67-7.71 (m, 1H), 7.59-7.62 (m, 2H), 7.49 (s, 1H), 7.40 (d, 1H), 7.37(s, 1H), 7.32 (s, 1H), 7.21 (dd, 1H), 6.89 (s, 1H), 6.68 (dd, 1H), 6.16(d, 1H), 3.74 (s, 3H), 3.01 (s, 3H), 1.28 (s, 9H).

LCMS m/z 670 (M+H)⁺ (ES⁺)

Example 31N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)amino)-pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

(i) 1-(2-Methoxy-4-nitrophenyl)pyridin-2(1H)-one

To a stirred solution of 1-fluoro-2-methoxy-4-nitrobenzene (250 mg,1.461 mmol) and 2-hydroxypyridine (140 mg, 1.472 mmol) in DMF (4 mL) wasadded cesium carbonate (625 mg, 1.918 mmol). The mixture was heated to120° C. and stirred overnight. The reaction was cooled to rt andquenched with water (15 mL). On standing, a solid slowly precipitatedfrom the mixture and was removed by filtration, washing with additionalwater. The filtrate was extracted with DCM and the organic phase driedvia hydrophobic frit and concentrated in vacuo affording a yellow oil.The oil was purified by chromatography on the Companion (24 g column,0.5-3% MeOH in DCM) to afford the sub-title compound (92 mg) as a yellowsolid.

LCMS m/z 247 (M+H)⁺ (ES⁺)

(ii) 1-(4-Amino-2-methoxyphenyl)pyridin-2(1H)-one

The product from step (i) above (120 mg, 0.487 mmol) was dissolved inethanol (4 mL) and Fe powder (250 mg, 4.48 mmol) was added followed by asolution of NH₄Cl (30 mg, 0.561 mmol) in water (1 mL). The resultingsuspension was heated at 80° C. for 2 h. The reaction was cooled to rtand filtered through Celite. The filtrate was concentrated in vacuoaffording a green solid. The material was sonicated in EtOAc (5 mL) andDCM (20 mL) for 5 mins, then filtered and the filtrate concentrated invacuo affording the sub-title compound (110 mg) as a yellow solid.

LCMS m/z 217 (M+H)⁺ (ES⁺)

(iii)N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide

A suspension of the product from step (ii) above (36 mg, 0.166 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 100 mg, 0.162 mmol), K₂CO₃ (70 mg, 0.506 mmol),and BrettPhos G3 precatalyst (5 mg, 5.52 μmol) in DMF (3 mL) wasdegassed with nitrogen for 10 mins. The reaction was then heated undernitrogen at 85° C. (block temperature) for 2 h. The reaction was cooledand partitioned between EtOAc (10 mL) and water (10 mL). The aqueousphase was extracted with EtOAc (5 mL). The combined organic phase waswashed with brine (5 mL) then dried (MgSO₄), filtered and concentratedin vacuo affording a dark yellow oil. The crude product was purified bychromatography on the Companion (12 g column, 1-6% MeOH in DCM) toafford the title compound (94 mg) as a pale beige foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.14 (s, 2H), 8.91 (s, 1H),8.31 (d, 1H), 8.20 (d, 1H), 8.11-8.14 (m, 2H), 7.89 (d, 1H), 7.70-7.73(m, 1H), 7.61-7.64 (m, 1H), 7.51 (d, 1H), 7.40-7.47 (m, 3H), 7.27 (dd,1H), 7.03-7.06 (m, 2H), 6.62 (dd, 1H), 6.41 (d, 1H), 6.21 (t, 1H), 6.14(d, 1H), 3.81 (s, 3H), 3.66 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 749 (M+H)⁺ (ES⁺)

Example 325-(tert-Butyl)-N-(2-hydroxyethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide

(i)4-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt

To a stirred solution of methyl4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate(see Example 1(ii) above; 1 g, 1.940 mmol) in THF (5 mL) and MeOH (2 mL)was added LiOH (0.065 g, 2.72 mmol) and water (2 mL) and the reactionleft stirring overnight at 40° C. The reaction was concentrated in vacuoaffording a pale brown foam. The foam was suspended in water (5 mL) andacidified with 1M HCl (6 mL) resulting in the formation of a palesuspension. The solid was recovered by filtration washing with wateruntil the filtrate was pH 2. The cake was washed with isohexane toremove excess water and dried to afford the sub-title compound (1 g).

¹H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.40 (s, 1H), 8.38-8.04 (m,2H), 7.91-7.75 (m, 1H), 7.73-7.54 (m, 4H), 7.45-7.31 (m, 2H), 7.11 (dd,1H), 6.75 (dd, 1H), 6.22 (d, 1H), 3.74 (s, 3H), 1.52 (s, 9H).

LCMS m/z 502 (M+H)⁺ (ES⁺)

(ii) tert-Butyl(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)carbamoyl)phenyl)-amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

HATU (1 g, 2.63 mmol) was added to a solution of the product from step(i) above (1 g, 1.859 mmol), 4-(2-aminoethyl)thiomorpholine 1-oxide,hydrochloride salt (500 mg, 2.52 mmol) and Hünig's base (1.5 mL, 8.59mmol) in DMF (7.5 mL). The reaction mixture was stirred at rt for 16 h.The mixture was poured into water (100 mL) and partitioned with DCM 2×(50 mL). The organics were separated, bulked, dried (MgSO₄), filteredand evaporated to a brown gum. The crude product was purified bychromatography on silica gel (12 g column, 2% MeOH:DCM to 10%) to affordthe sub-title compound (800 mg) as a tan solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.28 (s, 1H), 8.34-8.01 (m,3H), 7.84 (d, 1H), 7.76 (d, 1H), 7.70-7.53 (m, 4H), 7.37 (d, 1H), 7.22(dd, 1H), 6.66 (dd, 1H), 6.13 (d, 1H), 3.86 (s, 3H), 3.39 (q, 2H),3.05-2.82 (m, 4H), 2.82-2.65 (m, 4H), 2.55 (t, 2H), 1.53 (s, 9H).

LCMS m/z 646 (M+H)⁺ (ES⁺)

(iii)4-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide

TFA (1 mL, 12.98 mmol) was added to a solution of the product from step(ii) above (800 mg, 1.239 mmol) in DCM (10 mL) and the reaction stirredovernight. The solvents were evaporated and the residue was loaded ontoa column of SCX (10 g) in MeOH. The column was washed with MeOH and thenthe product was eluted with 0.7 M ammonia in MeOH. The resultant mixturewas concentrated in vacuo to afford the sub-title compound (650 mg) as atan solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.35-7.98 (m, 3H), 7.75 (d,1H), 7.68-7.59 (m, 1H), 7.59-7.50 (m, 1H), 7.50-7.36 (m, 2H), 7.20 (dd,1H), 7.11 (dd, 1H), 6.72 (dd, 1H), 6.60 (dd, 1H), 6.08 (d, 1H), 5.84 (s,2H), 3.84 (d, 3H), 3.39 (q, 2H), 3.04-2.82 (m, 4H), 2.78-2.62 (m, 4H),2.55 (t, 2H).

LCMS m/z 546 (M+H)⁺ (ES⁺)

(iv) Methyl5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)-ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoate

A solution of methyl5-(tert-butyl)-2-methoxy-3-((phenoxycarbonyl)amino)benzoate (see, forexample, Baker, T. et al., WO 2014/162126, 9 Oct. 2014; 500 mg, 1.399mmol) and the product from step (iii) above (650 mg, 1.191 mmol) and TEA(40 μL, 0.287 mmol) in THF (10 mL) was heated at 60° C. (blocktemperature) for 16 h. The solvent was evaporated and the crude productwas purified by chromatography on silica gel (40 g column, 2% MeOH:DCMto 10%) to afford the sub-title compound (625 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.27 (s, 1H), 8.97 (s, 1H),8.61 (d, 1H), 8.31 (d, 1H), 8.20-8.06 (m, 3H), 7.88 (d, 1H), 7.78-7.68(m, 2H), 7.62 (t, 1H), 7.58 (d, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 7.23(dd, 1H), 6.66 (dd, 1H), 6.16 (d, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85(s, 3H), 3.39 (q, 2H), 3.03-2.81 (m, 4H), 2.80-2.64 (m, 4H), 2.55 (t,2H), 1.29 (s, 9H).

LCMS m/z 809 (M+H)⁺ (ES⁺)

(v)5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)-carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoicacid, hydrochloride salt

To a stirred solution of the product from step (iv) above (620 mg, 0.766mmol) in THF (5 mL) and MeOH (2 mL) was added LiOH (25 mg, 1.044 mmol)and water (2 mL) and the reaction left stirring overnight at 40° C. Thereaction was concentrated in vacuo affording a pale brown foam. The foamwas suspended in water (5 mL) and acidified with HCl (100 μL, 1.170mmol), the resulting solution was pH 1-2. The desired compound wasrecovered by freeze drying to afford the sub-title compound (650 mg).

LCMS m/z 795 (M+H)⁺ (ES⁺)

(vi)5-(tert-Butyl)-N-(2-hydroxyethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-4-((2-(1-oxidothiomorpholino)ethyl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide

HATU (75 mg, 0.197 mmol) was added to a solution of the product fromstep (v) above (110 mg, 0.119 mmol), 2-aminoethanol (20 μL, 0.331 mmol)and Hünig's base (80 μL, 0.458 mmol) in DMF (2 mL). The reaction mixturewas stirred at rt for 1 h. The mixture was poured into water (10 mL) andpartitioned repeatedly with 10% MeOH:DCM (6×10 mL). The organics wereseparated, bulked, dried (MgSO₄), filtered and evaporated to a browngum. The crude product was purified by chromatography on silica gel (12g column, 2% MeOH:DCM to 20%) to afford the title compound (80 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.28 (s, 1H), 8.95 (s, 1H),8.46 (d, 1H), 8.32 (d, 1H), 8.26 (t, 1H), 8.21-8.04 (m, 3H), 7.87 (d,1H), 7.76 (d, 1H), 7.72 (t, 1H), 7.62 (t, 1H), 7.58 (s, 1H), 7.41 (d,1H), 7.30-7.15 (m, 2H), 6.66 (dd, 1H), 6.16 (d, 1H), 4.80 (t, 1H), 3.86(s, 3H), 3.82 (s, 3H), 3.57 (q, 2H), 3.39 (q, 4H), 3.04-2.81 (m, 4H),2.80-2.63 (m, 4H), 2.55 (s, 2H), 1.29 (s, 9H).

LCMS m/z 838 (M+H)⁺ (ES⁺)

Example 334-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)morpholine4-oxide

HATU (120 mg, 0.316 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 150 mg, 0.204 mmol),4-(2-aminoethyl)morpholine 4-oxide (John, V. and Maillard, M., WO2003/103653; 40 mg, 0.246 mmol) and Hünig's base (150 μL, 0.859 mmol) inDMF (2 mL) at rt. The mixture was stirred for 2 h then concentrated invacuo affording a brown oil. 100 mg of the crude material was purifiedby preparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford the title compound (10 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.62 (s, 1H), 9.41 (s, 1H), 9.23 (s, 1H),9.13 (s, 1H), 8.95 (s, 1H), 8.30 (d, 1H), 8.09-8.18 (m, 3H), 7.86 (d,1H), 7.74-7.68 (m, 2H), 7.59-7.68 (m, 1H), 7.52 (s, 1H), 7.37-7.40 (m,1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.63-6.64 (m, 1H), 6.14 (s, 1H), 4.15(t, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.65-3.74 (m, 4H), 4H under H2O,3.09 (s, 3H), 3.01 (d, 2H), 1.26 (s, 9H).

LCMS m/z 828 (M+H)⁺ (ES⁺)

Example 347-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)heptanoicacid

(i) Methyl7-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)heptanoate

HATU (120 mg, 0.316 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 150 mg, 0.204 mmol),methyl 7-aminoheptanoate, hydrochloride salt (50 mg, 0.256 mmol) andHünig's base (150 μL, 0.859 mmol) in DMF (2 mL) at rt. The mixture wasstirred overnight. The mixture was poured into water (10 mL) resultingin the precipitation of a white solid. The solid was isolated byfiltration, washing with additional water, then the solid dried at 50°C. The crude product was purified by chromatography on the Companion (12g column, 1-5% MeOH in DCM) to afford the sub-title compound (120 mg) asa white solid.

LCMS m/z 841 (M+H)⁺ (ES⁺)

(ii)7-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)heptanoicacid, hydrochloride salt

To a stirred solution of the product from step (i) above (120 mg, 0.143mmol) in THF (5 mL) was added NaOH (2M aq.) (1.5 mL, 3.00 mmol). MeOH (1mL) was added and stirring continued overnight. The reaction wasconcentrated in vacuo affording a yellow solid. The material wasacidified with 1M HCl causing a pink solid to precipitate. The solid wascollected by filtration, washing with water. The resulting solid wasdried at 40° C. under vacuum to afford the title compound (115 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1H), 9.54 (s, 1H), 9.14 (s, 1H),8.99 (s, 1H), 8.36 (d, 1H), 8.11-8.18 (m, 3H), 8.00 (t, 1H), 7.86 (d,1H), 7.70-7.74 (m, 2H), 7.62-7.66 (m, 1H), 7.44 (d, 1H), 7.37 (s, 1H),7.10 (d, 1H), 7.03 (d, 1H), 6.77 (d, 1H), 6.24 (s, 1H), 3.83 (s, 3H),3.81 (s, 3H), 3.24 (q, 2H), 3.10 (s, 3H), 2.20 (s, 2H), 1.42-1.56 (m,4H), 1.27 (s, 9H), 1.22-1.36 (m, 4H).

LCMS m/z 827 (M+H)⁺ (ES⁺)

Example 352-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyldihydrogen phosphate

(i) Di-tert-butyl(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyl)phosphate

HATU (108 mg, 0.285 mmol) was added to a solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 150 mg, 0.204 mmol),2-aminoethyl di-tert-butyl phosphate (100 mg, 0.395 mmol) and Hünig'sbase (107 μL, 0.611 mmol) in DMF (1 mL). The reaction mixture wasstirred at rt for 16 h. HATU (20 mg) was added to the reaction mixture,and the mixture was stirred for a further 4 hours. The mixture waspoured into water (20 mL) and partitioned repeatedly with 10% MeOH:DCM(5×10 mL). The organics were separated, bulked, dried (MgSO₄), filteredand evaporated to a yellow oil. The crude product was purified bychromatography on the Companion (4 g column, 0-10% MeOH in iso-hexane)to afford the sub-title compound (205 mg) as a thick tan oil.

LCMS m/z 935 (M+H)⁺ (ES⁺)

(ii)2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzamido)ethyldihydrogen phosphate

TFA (0.2 mL, 2.60 mmol) was added to a solution of the product from step(i) above (200 mg, 0.214 mmol) in DCM (2 mL). The reaction mixture wasstirred at rt for one hour then concentrated in vacuo. The crude productwas loaded onto a column of SCX (3 g) in MeOH. The column was washedwith MeOH and then the product was eluted with 0.7 M ammonia in MeOH.The resultant mixture was concentrated in vacuo and the residuetriturated with acetonitrile (2 mL). The resultant solid was filteredand dried in vacuo to afford the ammonium salt of the title compound (77mg) as an off-white solid.

¹H NMR (of ammonium salt; 400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.26 (s,1H), 9.04 (s, 1H), 8.33 (d, 1H), 8.24 (t, 1H), 8.16-8.14 (m, 2H), 8.08(d, 1H), 7.85 (d, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 7.58 (dd, 1H), 7.42(s, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 7.01 (d, 1H), 6.65 (dd, 1H), 6.14(d, 1H), 3.82 (s, 3H), 3.81-3.76 (m, 2H), 3.74 (s, 3H), 3.41 (q, 2H),3.08 (s, 3H), 1.26 (s, 9H).

LCMS (of ammonium salt) m/z 823 (M+H)⁺ (ES⁺); 821 (M−H)⁻ (ES⁻)

The ammonium salt (77 mg, 0.092 mmol) was loaded onto a column of Dowex50WX2 Na⁺ form (4 g) in water (2 mL). The column was eluted with water(10 mL) to get the sodium salt. The product-rich fractions were freezedried to afford the sodium salt of the title compound (40 mg) as acolourless solid.

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.25 (s, 1H),9.08 (bs, 2H), 8.34 (d, 1H), 8.24 (t, 1H), 8.16-8.15 (m, 2H), 8.05 (d,1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.66 (dd, 1H), 7.57 (dd, 1H), 7.38-7.36(m, 2H), 7.15 (d, 1H), 7.01 (d, 1H), 6.66 (dd, 1H), 6.14 (d, 1H), 3.83(s, 3H), 3.82-3.80 (m, 2H), 3.71 (s, 3H), 3.44-3.41 (m, 2H), 3.08 (s,3H), 1.26 (s, 9H).

LCMS (of sodium salt) m/z 823 (M+H)⁺ (ES⁺)

Example 364-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,6-dimethoxybenzamide

(i) tert-Butyl(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamoyl)-3,5-dimethoxyphenyl)carbamate

HATU (300 mg, 0.789 mmol) was added to a solution of4-((tert-butoxycarbonyl)amino)-2,6-dimethoxybenzoic acid (see Example22(ii) above; 200 mg, 0.673 mmol), 2-(2-(2-aminoethoxy)ethoxy)ethanol(150 mg, 1.005 mmol) and Hünig's base (400 μL, 2.290 mmol) in DCM (5 mL)and DMF (1 mL). The reaction mixture was stirred at rt for 16 h. Themixture was partitioned between DCM (15 mL) and water (15 mL). Theorganics were separated, dried (MgSO₄) filtered and evaporated to give ayellow gum which was pre-absorbed onto silica (4 g) and purified bychromatography on silica gel (12 g column, 2% MeOH:DCM to 10%) to affordthe sub-title compound (190 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.87 (t, 1H), 6.83 (s, 2H),4.58 (t, 1H), 3.66 (s, 6H), 3.59-3.37 (m, 10H), 3.27 (q, 2H), 1.48 (s,9H).

LCMS m/z 429 (M+H)⁺ (ES⁺)

(ii)4-Amino-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,6-dimethoxybenzamide

TFA (350 μL, 4.54 mmol) was added to a solution of the product from step(i) above (180 mg, 0.420 mmol) in DCM (2 mL) and the reaction leftstirring for 72 h. The reaction was found to contain a mixture ofstarting material and trifluoroacetic ester. The mixture was redissolvedin DCM (2 mL) and TFA (1 mL) added. The reaction was stirred for 3 h andsolvents evaporated. The residue was refluxed in MeOH and K₂CO₃ (200 mg,1.447 mmol) for 1 h, cooled and filtered. The filtrate was evaporated toafford the sub-title compound (150 mg) as a yellow gum.

LCMS m/z 329 (M+H)⁺ (ES⁺); 85% purity @ 254 nm.

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,6-dimethoxybenzamideMethod 1

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 150 mg, 0.264 mmol), the product from step (ii)above (150 mg, 0.388 mmol), K₂CO₃ (100 mg, 0.724 mmol), and BrettPhos G1Precatalyst (5 mg, 5.64 μmol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (2 mL) was added and the stirred suspensionwas degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 1 h. The mixture was cooled to rt and filtered. The crude productwas purified by preparative HPLC (Varian, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,20-50% MeCN in Water) to afford the title compound (95 mg) as acolourless solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.07 (s, br, 1H), 9.02 (s,1H), 8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.14-8.05 (m, 2H),7.92-7.85 (m, 1H), 7.82 (t, 1H), 7.76-7.66 (m, 1H), 7.66-7.57 (m, 1H),7.39 (d, 1H), 7.03 (d, 1H), 6.94 (s, 2H), 6.61 (dd, 1H), 6.11 (d, 1H),4.57 (t, 1H), 3.81 (s, 3H), 3.61 (s, 6H), 3.56-3.36 (m, 10H), 3.26 (q,2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 861 (M+H)⁺ (ES⁺)

Method 2

A solution of4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxy-benzoicacid (see Example 46 below; 15 g, 18.91 mmol), Hünig's base (14 mL, 80mmol) and HATU (7.2 g, 18.94 mmol) in NMP (200 mL) was stirred at rt for30 mins. Additional HATU (3.0 g) was added and stirring continued for 10mins. 2-(2-(2-aminoethoxy)ethoxy)ethanol (3.7 g, 24.80 mmol) was addedand the reaction stirred for 10 mins. The reaction was then heated to40° C. for 2 h then cooled to rt and stirred overnight. The reaction waspartitioned between EtOAc (300 mL) and water (400 mL). The aqueous phasewas extracted with EtOAc (100 mL) and the combined organics washed withwater (2×300 mL) then dried (MgSO₄), filtered and concentrated in vacuoaffording a yellow foam. The crude product was purified bychromatography on the Companion (220 g column, 1-10% MeOH in DCM) toafford the sub-title compound as an off-white foam. On standing, a largeamount of a dark coloured oil precipitated from the combined aqueouslayer. LCMS analysis showed this to be predominantly the product. Mostof the aqueous material was decanted off and the oil diluted with EtOAc.Only some of the oil was solubilised so MeOH (˜ 1/10 the volume ofEtOAc) was added. The resulting solution was washed with water (10 mL).The combined aqueous phase was re-extracted with 10% MeOH in EtOAc andthe organics combined, washed with water (100 mL), dried (MgSO₄),filtered and concentrated in vacuo affording a beige foam. The crudeproduct was purified by chromatography on the Companion (220 g column,1-10% MeOH in DCM) affording the sub title compound as an off-whitefoam. The two batches were combined in DCM and re-concentrated affordingthe title compound (11.46 g) as an off-white foam.

LCMS m/z 861 (M+H)⁺ (ES⁺)

Example 374-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-2,6-dimethoxybenzamide

(i) tert-Butyl(4-((2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)carbamoyl)-3,5-dimethoxyphenyl)carbamate

HATU (300 mg, 0.789 mmol) was added to a solution of4-((tert-butoxycarbonyl)amino)-2,6-dimethoxybenzoic acid (see Example22(ii) above; 200 mg, 0.673 mmol),2-(4-(2-aminoethyl)piperazin-1-yl)ethanol (150 mg, 0.866 mmol) andHünig's base (400 μL, 2.290 mmol) in DCM (5 mL) and DMF (1 mL). Thereaction mixture was stirred at rt for 16 h. The mixture was partitionedbetween DCM (15 mL) and water (15 mL). The organics were separated,dried (MgSO₄) filtered and evaporated to give a yellow gum which waspre-absorbed onto silica (4 g) and purified by chromatography on silicagel (12 g column, 2% MeOH:DCM to 10% then 10% 7N NH₃ MeOH:DCM) to affordthe sub-title compound (110 mg).

¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.74 (t, 1H), 6.83 (s, 2H),4.48 (s, 1H), 3.66 (s, 6H), 3.60-3.45 (m, 2H), 3.24 (q, 2H), 2.49-2.34(m, 12H), 1.48 (s, 9H).

LCMS m/z 453 (M+H)⁺ (ES⁺)

(ii)4-Amino-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-2,6-dimethoxybenzamide,2TFA

TFA (200 μL, 2.60 mmol) was added to a solution of the product from step(i) above (110 mg, 0.243 mmol) in DCM (1 mL) and the reaction leftstirring for 72 h. The solvents were evaporated and the residueazeotroped with toluene to afford the sub-title compound (120 mg) as apale brown gum.

LCMS m/z 353 (M+H)⁺ (ES⁺); 85% purity @ 254 nm.

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-2,6-dimethoxybenzamide

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 110 mg, 0.193 mmol), the product from step (ii)above (110 mg, 0.190 mmol), K₂CO₃ (150 mg, 1.085 mmol), and BrettPhos G1Precatalyst (5 mg, 5.64 μmol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (2 mL) was added and the stirred suspensionwas degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 16 h. The mixture was cooled to rt and filtered. The crude productwas purified by preparative HPLC (Varian, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,20-50% MeCN in Water) to afford the title compound (35 mg) as a pale tansolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.14 (s, 1H), 9.02 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.12 (t, 2H), 7.87 (d, 1H),7.77-7.53 (m, 3H), 7.39 (d, 1H), 7.03 (d, 1H), 6.94 (s, 2H), 6.61 (dd,1H), 6.11 (d, 1H), 4.40 (s, br, 1H), 3.81 (s, 3H), 3.61 (s, 6H),3.55-3.42 (m, 2H), 3.22 (q, 2H), 3.10 (s, 3H), 2.48-2.21 (m, 8H), 1.27(s, 9H). 4H under water peak at 3.32 ppm.

LCMS m/z 885 (M+H)⁺ (ES⁺)

Example 384-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,2-bis(hydroxymethyl)propyl)-2-methoxybenzamide

HATU (80 mg, 0.210 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 100 mg, 0.136 mmol),2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol (22 mg, 0.163 mmol)and Hünig's base (120 μL, 0.687 mmol) in DMF (2 mL) at rt. The mixturewas stirred overnight then poured into water (10 mL) and partitionedwith EtOAc (10 mL). The organic phase was concentrated in vacuoaffording a pale yellow oil. The crude product was purified bypreparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford the title compound (45 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.27 (s, 1H), 9.7 (s, 1H),8.91 (s, 1H), 8.48 (t, 1H), 8.31 (d, 1H), 8.16-8.18 (m, 2H), 8.12 (d,1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.69-7.73 (m, 1H), 7.60-7.63 (m, 2H),7.40 (d, 1H), 7.22 (dd, 1H), 7.03 (d, 1H), 6.66 (dd, 1H), 6.16 (d, 1H),4.49 (t, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 8H under H₂O, 3.08 (s, 3H),1.27 (s, 9H).

LCMS m/z 817 (M+H)⁺ (ES⁺)

Example 394-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-2,6-dimethoxybenzamide

(i) tert-Butyl(4-((2-(dimethylamino)ethyl)carbamoyl)-3,5-dimethoxyphenyl)carbamate

HATU (1 g, 2.63 mmol) was added to a solution of4-((tert-butoxycarbonyl)amino)-2,6-dimethoxybenzoic acid (see Example22(ii) above; 300 mg, 1.009 mmol), N1,N1-dimethylethane-1,2-diamine (400μL, 3.66 mmol) and Hünig's base (500 μL, 2.86 mmol) in DMF (5 mL). Thereaction mixture was stirred at rt for 1 h. The mixture was partitionedbetween DCM (15 mL) and water (15 mL). The organics were separated,dried (MgSO₄) filtered and evaporated to give a yellow gum which waspre-absorbed onto silica (4 g) and purified by chromatography on silicagel (12 g column, 2% MeOH:DCM to 20%) to give a yellow gum. Thismaterial was redissolved in EtOAc (20 mL) and washed with water (20 mL).The organics were separated, dried (MgSO₄) filtered and the solventevaporated to afford the sub-title compound (220 mg) as a tan glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.98 (t, 1H), 6.85 (s, 2H),3.67 (s, 6H), 3.03-2.83 (m, 2H), 2.83-2.66 (m, 2H), 1.48 (s, 9H).—N(CH3)2 obscured by water peak 3.32 ppm.

LCMS m/z 368 (M+H)⁺ (ES⁺)

(ii) 4-Amino-N-(2-(dimethylamino)ethyl)-2,6-dimethoxybenzamide,bis(trifluoroacetate) salt

TFA (1 mL, 12.98 mmol) was added to a solution of the product from step(i) above (220 mg, 0.599 mmol) in DCM (2 mL) and the reaction leftstirring for 16 h. The solvents were evaporated to afford the sub-titlecompound (200 mg)

LCMS m/z 268 (M+H)⁺ (ES⁺)

(iii)4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-2,6-dimethoxybenzamide

A mixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 150 mg, 0.264 mmol), the product from step (ii)above (200 mg, 0.404 mmol), K₂CO₃ (200 mg, 1.447 mmol), and BrettPhos G1precatalyst (10 mg, 0.011 mmol) were degassed under vacuum back-fillingwith nitrogen 3 times. DMF (2 mL) was added and the stirred suspensionwas degassed under vacuum back-filling with nitrogen 3 times. Thereaction was then heated under nitrogen at 85° C. (block temperature)for 16 h. BrettPhos G1 Precatalyst (100 mg, 0.113 mmol) was added andstirring at 80° C. was continued for a further 4 h. The mixture wascooled to rt and filtered. The crude product was purified by preparativeHPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 am, 19×50 mm column, 20-50% MeCN in Water) to afford thetitle compound (30 mg) as a tan solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.11 (s, 1H), 9.02 (s, 1H),8.88 (s, 1H), 8.30 (d, 1H), 8.25-8.00 (m, 3H), 7.96-7.79 (m, 1H),7.78-7.51 (m, 3H), 7.39 (d, 1H), 7.03 (d, 1H), 6.93 (s, 2H), 6.61 (dd,1H), 6.11 (d, 1H), 3.81 (s, 3H), 3.61 (s, 6H), 3.19 (q, 2H), 3.04 (s,3H), 2.31 (t, 2H), 2.15 (s, 6H), 1.26 (s, 9H).

LCMS m/z 800 (M+H)⁺ (ES⁺)

Example 40N-(5-(tert-Butyl)-3-(3-(4-((2-((4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide

(i)(2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethyl)(2-methoxy-4-nitrophenyl)sulfane

((2-(2-(2-Bromoethoxy)ethoxy)ethoxy)methyl)benzene (1310 mg, 3.89 mmol)was added to a solution of 2-methoxy-4-nitrobenzenethiol (600 mg, 3.24mmol) and K₂CO₃ (493 mg, 3.56 mmol) in acetone (10 mL). The reactionmixture was stirred at rt for 17 hours. The reaction mixture wasconcentrated in vacuo, diluted with EtOAc (10 mL), washed with 5 wt % aqNaOH (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to afford a yellow oil. The crude product waspurified by chromatography on the Companion (40 g column, 0-100% ethylacetate in iso-hexane) to afford the sub-title compound (1.055 g) as asticky yellow-brown oil.

¹H NMR (400 MHz, DMSO-d6) δ 7.83 (dd, 1H), 7.69 (d, 1H), 7.45 (d, 1H),7.35-7.25 (m, 5H), 4.47 (s, 2H), 3.94 (s, 3H), 3.68 (t, 2H), 3.58-3.52(m, 8H), 3.23 (t, 2H).

(ii)1-((2-(2-(2-(Benzyloxy)ethoxy)ethoxy)ethyl)sulfonyl)-2-methoxy-4-nitrobenzene

mCPBA (616 mg, 2.75 mmol) was added slowly to an ice cold solution ofthe product from step (i) above (500 mg, 1.227 mmol) in DCM (5 mL). Thereaction was stirred at 0° C. for 30 min. then allowed to warm to rt andstirred for 1 h. The reaction mixture was filtered and the filtrateimmediately partitioned with sodium bisulphite solution 20% w/w (5 mL).The organic layer was separated, washed with sat. NaHCO₃ soln. (5 mL),dried (MgSO₄), filtered and the solvent evaporated to a yellow oil. Thecrude product was purified by chromatography on silica gel (12 g column,0-70% EtOAc in iso-hexane) to afford the sub-title compound (456 mg) asa pale yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ 8.03-7.94 (m, 3H), 7.37-7.28 (m, 5H), 4.45(s, 2H), 4.04 (s, 3H), 3.76-3.73 (m, 2H), 3.70-3.67 (m, 2H), 3.47-3.45(m, 2H), 3.38-3.36 (m, 2H), 3.28-3.26 (m, 2H), 3.18-3.16 (m, 2H).

LCMS m/z 440 (M+H)⁺ (ES⁺)

(iii) 2-(2-(2-((4-Amino-2-methoxyphenyl)sulfonyl)ethoxy)ethoxy)ethanol

A suspension of the product from step (ii) above (456 mg, 1.038 mmol)and 5% Pd/C (50% paste with water, 120 mg) in ethanol (5 mL) was stirredunder hydrogen (5 bar) for 2 h. The reaction mixture was filtered(Whatmans GF/F) and the filtrate evaporated to give partially reducedproduct. A suspension of the crude product and 5% Pd/C (50% paste withwater, 120 mg) in ethanol (5 mL) was stirred under hydrogen (5 bar) for2 h. The reaction mixture was filtered (Whatmans GF/F) and the filtrateevaporated to afford the sub-title compound (312 mg) as a thick orangeoil.

¹H NMR (400 MHz, DMSO-d6) δ 7.36 (d, 1H), 6.27 (s, 1H), 6.19 (d, 1H),6.11 (bs, 2H), 3.80 (s, 3H), 3.59 (t, 2H), 3.47-3.43 (m, 6H), 3.38-3.34(m, 4H).

LCMS m/z 320 (M+H)⁺ (ES⁺)

(iv)N-(5-(tert-Butyl)-3-(3-(4-((2-((4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide

A suspension of the product from step (iii) above (67.3 mg, 0.211 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 100 mg, 0.176 mmol), K₂CO₃ (68.0 mg, 0.492mmol), and BrettPhos G3 precatalyst (5 mg, 5.52 mol) in DMF (7 mL) wasdegassed with nitrogen for 10 mins. The reaction was then heated undernitrogen at 85° C. (block temperature) for 2 h. The reaction mixture wasconcentrated in vacuo and the crude product was purified by preparativeHPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water) to afford thetitle compound (44 mg) as an off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.41 (s, 1H), 9.17 (s, 1H),8.94 (s, 1H), 8.30 (d, 1H), 8.20-8.18 (m, 2H), 8.13 (d, 1H), 7.85 (dd,1H), 7.71 (dd, 1H), 7.65-7.59 (m, 2H), 7.54 (d, 1H), 7.41 (d, 1H), 7.30(dd, 1H), 7.01 (d, 1H), 6.71 (dd, 1H), 6.17 (d, 1H), 4.54 (t, 1H), 3.84(s, 3H), 3.80 (s, 3H), 3.62-3.59 (m, 2H), 3.54-3.51 (m, 2H), 3.42-3.38(m, 2H), 3.32-3.27 (m, 6H), 3.09 (s, 3H), 1.26 (s, 9H).

LCMS m/z 852 (M+H)⁺ (ES⁺); 850 (M−H)⁻ (ES⁻)

Example 414-((4-((4-(3-(5-(tert-Butyl)-3-(2-hydroxyacetamido)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide

(i) 2-(Benzyloxy)-N-(5-(tert-butyl)-2-methoxy-3-nitrophenyl)acetamide

HATU (2.80 g, 7.36 mmol) was added to a mixture of5-(tert-butyl)-2-methoxy-3-nitroaniline (1.5 g, 6.69 mmol),2-(benzyloxy)acetic acid (1.3 g, 7.82 mmol) and Hünig's base (3.50 mL,20.07 mmol) in DMF (20 mL) and stirred at rt for 72 h. The mixture waspartitioned between ether (100 mL) and water (100 mL), the organic layerwashed with sat. aq NaHCO₃ (50 mL), brine (50 mL), dried (MgSO₄),filtered and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel (80 g column, 0-20% EtOAc/isohexane) toafford the sub-title compound (1.99 g) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.81 (s, 1H), 7.62 (s, 1H),7.45-7.36 (m, 5H), 4.72 (s, 2H), 4.19 (s, 2H), 3.86 (s, 3H), 1.36 (s,9H).

LCMS m/z 373 (M+H)⁺ (ES⁺); 371 (M−H)⁻ (ES⁻)

(ii) N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)-2-(benzyloxy)acetamide

A mixture of the product from step (i) above (1.9 g, 5.10 mmol), Fepowder (2.5 g, 44.8 mmol) and NH₄Cl (0.082 g, 1.531 mmol) in EtOH (25mL) and water (7 mL) was heated at 80° C. for 2 h. The mixture wasfiltered through celite and evaporated under reduced pressure. Theresidue was partitioned between EtOAc (80 mL) and sat aq NaHCO₃ (50 mL),the organic layer washed with brine (50 mL), dried (MgSO₄), filtered andevaporated to afford the sub-title compound (1.75 g) as an oil.

LCMS m/z 343 (M+H)⁺ (ES⁺); 341 (M−H)⁻ (ES⁻)

(iii) Phenyl(3-(2-(benzyloxy)acetamido)-5-(tert-butyl)-2-methoxyphenyl)carbamate

Phenyl chloroformate (200 μL, 1.594 mmol) was added to a mixture of theproduct from step (ii) above (500 mg, 1.460 mmol) and NaHCO₃ (370 mg,4.40 mmol) in DCM (6 mL) and THF (3 mL). The mixture was stirred for 3 hthen partitioned between DCM (50 mL) and water (40 mL), the organiclayer was washed with brine (20 ml), dried (MgSO₄), filtered andevaporated under reduced pressure. Used crude in next step.

¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.16 (d, 1H), 7.96 (s, 1H),7.44-7.34 (m, 8H), 7.29-7.20 (m, 3H), 4.71 (s, 2H), 4.17 (s, 2H), 3.76(s, 3H), 1.31 (s, 9H).

LCMS m/z 463 (M+H)⁺ (ES⁺)

(iv) Phenyl(5-(tert-butyl)-3-(2-hydroxyacetamido)-2-methoxyphenyl)carbamate

A mixture of the product from step (iii) above (430 mg, 0.930 mmol) and5% Pd—C (100 mg) in THF (8 mL) was hydrogenated at 4 bar (4×10⁵ Pa) for3 h. The solution was filtered to afford the sub-title compound as asolution in THF (8 mL) which was used crude in the next step.

LCMS m/z 373 (M+H)⁺ (ES⁺); 371 (M−H)⁻ (ES⁻)

(v)4-((4-((4-(3-(5-(tert-Butyl)-3-(2-hydroxyacetamido)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide

Et₃N (25 μL, 0.179 mmol) and4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide(see Example 32(iii) above; 254 mg, 0.465 mmol) were added to a solutionof the product from step (iv) above (0.465 mmol) in THF (4 mL). Themixture was heated at 60° C. for 24 h then evaporated under reducedpressure. The residue was purified by chromatography on silica gel (40 gcolumn, 0-15% MeOH/DCM) to afford a solid that was triturated with MeCN,filtered and dried to afford the title compound (50 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.28 (s, 1H), 9.19 (s, 1H),8.89 (s, 1H), 8.31 (d, 1H), 8.18-8.11 (m, 4H), 7.96 (d, 1H), 7.87 (d,1H), 7.76 (d, 1H), 7.74-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.57 (d, 1H),7.43 (d, 1H), 7.22 (dd, 1H), 6.66 (dd, 1H), 6.20-6.15 (m, 2H), 4.04 (d,2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.41-3.36 (m, 2H), 2.96-2.84 (m, 4H),2.75-2.68 (m, 4H), 2.55 (t, 2H), 1.27 (s, 9H).

LCMS m/z 824 (M+H)⁺ (ES⁺); 822 (M−H)⁻ (ES⁻)

Example 424-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-((2S,3S4R)-2,3,4,5-tetrahydroxypentyl)benzamide

HATU (80 mg, 0.210 mmol) was added to a stirred solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoicacid, hydrochloride salt (see Example 1 above; 100 mg, 0.136 mmol),(2R,3S,4S)-5-aminopentane-1,2,3,4-tetraol (30 mg, 0.198 mmol) andHünig's base (120 μL, 0.687 mmol) in NMP (2 mL) at rt. The mixture wasstirred for 2 h. The reaction was repeated on a 50 mg scale, combinedand diluted with MeOH (2 mL). The mixture was loaded onto apre-conditioned cartridge of SCX resin. The resin was washed with MeOHthen the product released with 1% NH₃ in MeOH. The ammonia solution wasconcentrated in vacuo affording a pale yellow oil. The crude product waspurified by preparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate),Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN inWater) to afford the title compound (42 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H),8.93 (s, 1H), 8.26-8.32 (m, 2H), 8.16-8.19 (m, 2H), 8.13 (d, 1H), 7.87(d, 1H), 7.80 (d, 1H), 7.69-7.73 (m, 1H), 7.57-7.64 (m, 2H), 7.41 (d,1H), 7.23 (dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 4.96 (d,1H), 4.86 (d, 1H), 4.70 (d, 1H), 4.40 (t, 1H), 3.85 (s, 3H), 3.81 (s,3H), 3.65-3.70 (m, 1H), 3.51-3.62 (m, 3H), 3.37-3.43 (m, 2H), 3.26-3.32(m, 1H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 833 (M+H)⁺ (ES⁺)

Example 43 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

(i) Ethyl (2-methoxy-4-nitrophenyl)(methyl)phosphinate Method 1

A mixture of 1-iodo-2-methoxy-4-nitrobenzene (1 g, 3.58 mmol), Et₃N (1mL, 7.17 mmol), Pd(Ph₃P)₄ (0.166 g, 0.143 mmol) and ethylmethylphosphinate (see, for example, Chebib, M. et al., WO 2006/000043,5 Jan. 2006; 450 μL, 4.38 mmol) in toluene (15 mL) was degassed with N₂for 5 min the heated at 100° C. for 6 h. The mixture was partitionedbetween EtOAc (60 mL) and aq 1M HCl (60 mL), the organic layer washedwith water (50 mL), dried (MgSO₄), filtered and evaporated under reducedpressure. The crude product was purified by chromatography on silica gel(80 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound(224 mg) as a brown solid.

¹H NMR (400 MHz, CDCl₃) δ 8.18 (dd, 1H), 7.94 (dt, 1H), 7.80 (dd, 1H),4.14-4.05 (m, 1H), 4.04 (s, 3H), 3.89-3.79 (m, 1H), 1.80 (d, 3H), 1.29(t, 3H).

LCMS m/z 260 (M+H)⁺ (ES⁺)

Method 2

A solution of 1-iodo-2-methoxy-4-nitrobenzene (15 g, 53.8 mmol), DIPEA(30 mL, 172 mmol) and ethyl methylphosphinate (9.51 mL, 64.8 mmol) intoluene (100 mL) was vacuum degassed and back filled with N₂ threetimes. The reaction mixture was warmed to 50° C. XantPhos G3 precatalyst(1 g, 1.056 mmol) was added and the reaction heated under N₂ at 85° C.(internal temperature, 100° C. block temperature) for 1 h. The reactionmixture was cooled, preabsorbed onto silica (9.9 g) and purified bychromatography on silica gel (40 g column, 50% EtOAc:isohexane to 100%)to afford the sub-title compound (10 g) as a pale tan solid.

¹H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, 1H), 7.94 (dt, 1H), 7.88 (dd, 1H),4.01 (s, 3H), 3.98-3.85 (m, 1H), 3.81-3.68 (m, 1H), 1.71 (d, 3H), 1.16(t, 3H).

LCMS m/z 260 (M+H)⁺ (ES⁺)

(ii) Ethyl (4-amino-2-methoxyphenyl)(methyl)phosphinate

A mixture of the product from step (i) above (2.6 g, 10.03 mmol) and 5%Pd—C (50 mg) in EtOH (20 mL) was hydrogenated at 5 Bar (5×10⁵ Pa) for 2h. The mixture was filtered and the filtrate evaporated under reducedpressure to afford the sub title compound as a pale yellow gum (2.2 g).

¹H NMR (400 MHz, DMSO-d6) δ 7.35 (dd, 1H), 6.23-6.18 (m, 2H), 5.79 (s,2H), 3.81-3.56 (m, 2H), 3.73 (s, 3H), 1.51 (d, 3H), 1.11 (t, 3H).

LCMS m/z 230 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-(ethoxy(methyl)phosphoryl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 5 g, 13.48 mmol), the product from step (ii) above (2.6 g,11.34 mmol), potassium carbonate (6 g, 43.4 mmol), and BrettPhos G3precatalyst (0.3 g, 0.331 mmol) were degassed under vacuum, back-fillingwith N₂ 3 times. DMF (50 mL) was added and the stirred suspension wasdegassed under vacuum, back-filling with N₂ 3 times. The reaction wasthen heated under N₂ at 85° C. (internal temperature) for 1 h. Themixture was cooled to room temperature and filtered and the solventevaporated to give a dark oil. The crude product was preabsorbed ontosilica (20 g) and purified by chromatography on silica gel 120 g column,2% MeOH:DCM to 5%) to afford the sub-title compound (6.35 g) as a paletan glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.33 (s, 1H), 8.27-8.11 (m,2H), 7.84 (d, 1H), 7.65 (d, 1H), 7.63-7.49 (m, 4H), 7.38 (d, 1H), 7.27(dt, 1H), 6.67 (dd, 1H), 6.15 (d, 1H), 3.87-3.72 (m, 4H), 3.71-3.57 (m,1H), 1.57 (d, 3H), 1.53 (s, 9H), 1.12 (t, 3H).

LCMS m/z 564 (M+H)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

The product from step (iii) above (6.35 g, 10.93 mmol) was dissolved inDCM (50 mL) and TFA (5 mL, 64.9 mmol) added. The reaction mixture wasstirred at room temperature for 16 h. The solvents were evaporated andthe residue azeotroped with toluene. The crude product was loaded onto acolumn of SCX (60 g) in MeOH. The column was washed with MeOH and thenthe product was eluted with 0.7 M ammonia in MeOH. The resultant mixturewas concentrated in vacuo to afford the sub-title compound (5 g) as adark brown glass.

¹H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.24-8.13 (m, 1H), 8.11 (d,1H), 7.71-7.60 (m, 1H), 7.57-7.39 (m, 4H), 7.26 (dt, 1H), 7.11 (d, 1H),6.72 (d, 1H), 6.61 (dd, 1H), 6.10 (d, 1H), 5.85 (s, 2H), 3.84-3.77 (m,1H), 3.76 (s, 3H), 3.70-3.56 (m, 1H), 1.56 (d, 3H), 1.11 (t, 3H).

LCMS m/z 464 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinateMethod 1

A suspension of the product from step (ii) above (97 mg, 0.422 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 200 mg, 0.351 mmol), K₂CO₃ (136 mg, 0.984mmol), and BrettPhos G3 precatalyst (10 mg, 0.011 mmol) in DMF (7 mL)was degassed with nitrogen for 10 mins. The reaction was then heatedunder nitrogen at 85° C. (block temperature) for 2 h. The reaction wascooled to rt and added to water (10 mL). The organic layer was extractedwith DCM (10 mL), dried via a hydrophobic phase separator andconcentrated in vacuo. The crude product was purified by chromatographyon the Companion (4 g column, 1-8% MeOH in DCM) to afford a tan thinfilm (54 mg). The aqueous layer was further extracted with 10% MeOH inDCM (10 mL), dried via a hydrophobic phase separator and concentrated invacuo. Both fractions (column and second extraction) were combined toafford the title compound (94 mg) as a tan thin film.

LCMS m/z 762 (M+H)⁺ (ES⁺); 76% purity @ 254 nm.

Method 2

Triethylamine (300 μL, 2.152 mmol) was added to a warm solution ofphenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate(see Example 1(iv) above; 5 g, 12.74 mmol) and the product from step(iv) above (5 g, 10.25 mmol) in THF (50 mL) at 75° C. (blocktemperature) and the mixture stirred for 16 h. The solvents wereevaporated and the crude product was purified by chromatography onsilica gel (120 g column, 2% MeOH:DCM to 5%) to afford a pale tan glass.This material was stirred in THF (100 mL) for 16 h. The resulting solidwas filtered off and washed with ice cold THF (5 mL) to yield the titlecompound (4.88 g).

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.30 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.24-8.03 (m, 3H), 7.87 (d, 1H), 7.71 (t,1H), 7.62 (t, 1H), 7.57-7.45 (m, 2H), 7.40 (d, 1H), 7.27 (dt, 1H), 7.03(d, 1H), 6.66 (dd, 1H), 6.17 (d, 1H), 3.90-3.71 (m, 7H), 3.71-3.56 (m,1H), 3.10 (s, 3H), 1.56 (d, 3H), 1.27 (s, 9H), 1.11 (t, 3H).

LCMS m/z 762 (M+H)⁺ (ES⁺)

Example 44(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinicacid

Method 1

A solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 43 above; 94 mg, 0.091 mmol) in 1,4-dioxane (0.5 mL) wasstirred with aq. 1M NaOH (913 μL, 0.091 mmol) at rt. After 4 hours,another aliquot of NaOH was added (250 μL, 1M), and stirred overnight(18 hours) at rt. The reaction mixture was heated at 45° C. for 48 hoursthen concentrated in vacuo. The crude product was purified bypreparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford the title compound (13 mg) as a colourless powder.

¹H NMR (of ammonium salt; 400 MHz, DMSO-d6) δ 9.78 (bs, 1H), 9.15 (s,1H), 9.09 (s, 1H), 8.33 (d, 1H), 8.16-8.08 (m, 3H), 7.82 (d, 1H),7.63-7.47 (m, 3H), 7.37 (d, 1H), 7.25 (d, 1H), 7.11 (d, 1H), 7.00 (d,1H), 6.60 (dd, 1H), 6.08 (d, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.07 (s,3H), 1.33 (d, 3H), 1.25 (s, 9H).

LCMS (of ammonium salt) m/z 734 (M+H)⁺ (ES⁺); 732 (M−H)⁻ (ES⁻)

Method 2

A suspension of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(4.88 g, 6.28 mmol) in 1,4-dioxane (75 mL) and water (8 mL) was stirredwith sodium hydroxide 50% w/w (0.5 mL, 9.47 mmol) at 45° C. for 16 h.Analysis by LCMS showed 30% conversion. More sodium hydroxide 50% w/w(0.25 mL, 4.74 mmol) was added and heating continued to 48 h. Thereaction was cooled and acetic acid (0.75 mL, 13.10 mmol) was added. Thesolvents were evaporated and the residue purified by chromatography onreverse phase C18 (88 g column, 15%-75% MeCN: 10 mmol ammoniumbicarbonate soln.) to afford the title compound as the free acid (4 g).

¹H NMR (of free acid; 400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.22 (s, 1H),9.13 (s, 2H), 8.94 (s, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 8.16 (d, 1H),8.12 (d, 1H), 7.87 (d, 1H), 7.76-7.65 (m, 1H), 7.65-7.57 (m, 1H), 7.51(dd, 1H), 7.45-7.33 (m, 2H), 7.23 (dt, 1H), 7.03 (d, 1H), 6.64 (dd, 1H),6.15 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.10 (s, 3H), 1.47 (d, 3H),1.27 (s, 9H).

LCMS (of free acid) m/z 734 (M+H)⁺ (ES⁺)

The title compound (505 mg, 0.688 mmol) was suspended in water (5 mL).Sodium hydroxide 0.1 N (6 mL, 0.614 mmol) was added but an homogeneoussolution was not obtained. 0.7N NH₃ in MeOH (10 mL) was added and theresulting solution evaporated to a volume of circa 5 mL. This solutionwas loaded onto a column of Dowex 50WX2 Na⁺ form (50 g) and the columnwas washed with water (100 mL) to elute the title compound as the sodiumsalt.

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.75 (s, 1H),9.16 (s, 1H), 8.95 (s, 1H), 8.49 (d, 1H), 8.20-7.97 (m, 3H), 7.75 (d,1H), 7.58 (dd, 1H), 7.52-7.38 (m, 2H), 7.33 (d, 1H), 7.16-6.87 (m, 3H),6.59 (dd, 1H), 5.99 (d, 1H), 3.80 (s, 3H), 3.44 (s, 3H), 3.00 (s, 3H),1.45-1.03 (m, 12H).

LCMS (of sodium salt) m/z 734 (M+H)⁺ (ES⁺)

Example 45N-(5-(tert-Butyl)-3-(3-(4-((2-((4-((3-hydroxy-2,2-bis(hydroxymethyl)propyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide

(i)2-(Hydroxymethyl)-2-(((2-methoxy-4-nitrophenyl)thio)methyl)propane-1,3-diol

A mixture of 2-methoxy-4-nitrobenzenethiol (950 mg, 5.13 mmol), K₂CO₃(850 mg, 6.15 mmol) and2-(bromomethyl)-2-(hydroxymethyl)propane-1,3-diol (1225 mg, 6.16 mmol)in DMF (10 mL) was heated at 90° C. for 12 h. The mixture was cooled andpartitioned between EtOAc (80 mL) and water (80 mL), the organic layerseparated, dried (MgSO₄) and filtered. The MgSO₄ cake was washed withDCM (100 mL) and the combined filtrate evaporated under reducedpressure. The residue was triturated with ether (40 mL) and filtered toafford the sub-title compound (810 mg) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.90 (dd, 1H), 7.70 (d, 1H), 7.48 (d, 1H),4.57 (t, 3H), 3.99 (s, 3H), 3.44 (d, 6H), 2.99 (s, 2H).

LCMS m/z 326 (M+Na)⁺ (ES⁺)

(ii)2-(Hydroxymethyl)-2-(((2-methoxy-4-nitrophenyl)sulfonyl)methyl)propane-1,3-diol

mCPBA (1625 mg, 6.59 mmol) was added portionwise to a suspension of theproduct from step (i) above (800 mg, 2.64 mmol) in DCM (20 mL). Theresulting solution was stirred at rt for 4 h, evaporated to ˜10 mL thenpurified by chromatography on silica gel (80 g column, 0-10% MeOH/DCM)to afford the sub-title compound (638 mg) as a white solid.

LCMS m/z 336 (M+H)⁺ (ES⁺)

(iii)2-(((4-Amino-2-methoxyphenyl)sulfonyl)methyl)-2-(hydroxymethyl)propane-1,3-diol

A mixture of the product from step (ii) above (630 mg, 1.879 mmol) and5% Pd—C (100 mg) in THF (4 mL) and EtOH (4 mL) was hydrogenated at 2 bar(2×10⁵ Pa) for 3 days. The mixture was filtered and the solventevaporated to afford the sub-title compound (540 mg) as a sticky solid.

LCMS m/z 306 (M+H)⁺ (ES⁺)

(iv)N-(5-(tert-Butyl)-3-(3-(4-((2-((4-((3-hydroxy-2,2-bis(hydroxymethyl)propyl)sulfonyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide

A suspension of the product from step (iii) above (107 mg, 0.351 mmol),N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide(see Example 8(i) above; 200 mg, 0.351 mmol), K₂CO₃ (136 mg, 0.984mmol), and BrettPhos G3 precatalyst (10 mg, 0.011 mmol) in DMF (7 mL)was degassed with nitrogen for 10 mins. The reaction was then heatedunder nitrogen at 85° C. (block temperature) for 2 h. The reactionmixture was concentrated in vacuo and the crude product was purified bypreparative HPLC (Varian, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 20-50% MeCN in Water)to afford a pale tan foam. The product was purified by chromatography onthe Companion (4 g column, 1-10% MeOH in DCM, product elutes at 8%) toafford the title compound (103 mg) as a colourless powder.

¹H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.40 (s, 1H), 9.14 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.20-8.18 (m, 2H), 8.12 (d, 1H), 7.86 (d,1H), 7.71 (dd, 1H), 7.64-7.59 (m, 2H), 7.56 (d, 1H), 7.40 (d, 1H), 7.31(dd, 1H), 7.02 (d, 1H), 6.70 (dd, 1H), 6.18 (d, 1H), 4.34 (t, 3H), 3.84(s, 3H), 3.81 (s, 3H), 3.44-3.43 (m, 8H), 3.09 (s, 3H), 1.26 (s, 9H).

LCMS m/z 838 (M+H)⁺ (ES⁺); 836 (M−H)⁻ (ES⁻)

Example 464-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxybenzoicacid

(i) Benzyl 3-bromo-2,6-dimethoxybenzoate

Benzyl bromide (5 mL, 42.0 mmol) was added to a thick suspension of3-bromo-2,6-dimethoxybenzoic acid (9.4 g, 36.0 mmol) and K₂CO₃ (20 g,145 mmol) in DMF (300 mL). The mixture was heated at 70° C. (blocktemperature 55° C. internal) for 2 h. The reaction mixture wasconcentrated in vacuo to circa 20 mL then partitioned between diethylether (500 mL) and 20% w/w NaCl soln. (250 mL). The organics wereseparated, and washed successively with a 10% vol/vol solution of 880ammonia in water (250 mL) 1 N HCl (250 mL) and sat. NaHCO₃ (250 mL). Theorganics were separated, dried (MgSO₄), filtered and evaporated toafford the sub-title compound (12 g).

¹H NMR (400 MHz, DMSO-d6) δ 7.68 (d, 1H), 7.52-7.28 (m, 5H), 6.90 (d,1H), 5.35 (s, 2H), 3.79 (s, 3H), 3.70 (s, 3H).

LCMS m/z 351/353 (M+H)⁺ (ES⁺); BP 373/375 (M+Na)⁺ (ES⁺)

(ii) Benzyl 4-amino-2,6-dimethoxybenzoate

Sodium (4.5 g, 196 mmol) was added portionwise to a solution ofiron(III) chloride (50 mg, 0.308 mmol) in liquid ammonia (150 mL) overcirca 20 min. The dark grey suspension was stirred at reflux for 10minutes then cooled to −70° C. before dropwise addition of the productfrom step (i) above (16 g, 45.6 mmol) in THF (50 mL) over 5 min. Thereaction mixture was then allowed to reflux (circa −30° C.) for 90minutes before cooling to −50° C. and addition of NH₄Cl (12 g, 224mmol). The condenser was removed and the reaction allowed to evaporateovernight. The residue was partitioned between 1 N HCl (200 mL) and Et₂O(250 mL). The desired product as the hydrochloride salt was found inboth layers. The aqueous was separated and basified with NaOH (10 mL,189 mmol) to pH 8 then partitioned with Et₂O (300 mL). The organics wereseparated and bulked with the first Et₂O extract and washed with sat.NaHCO₃. The organics were separated, dried (MgSO₄), filtered andevaporate to a brown oil. The crude product was purified bychromatography on silica gel (120 g column, 10% EtOAc:isohexane to 50%)to afford the sub-title compound (8 g) as a tan solid.

¹H NMR (400 MHz, DMSO-d6) δ 7.44-7.28 (m, 5H), 5.86 (s, 2H), 5.55 (s,2H), 5.18 (s, 2H), 3.65 (s, 6H).

LCMS m/z 288 (M+H)⁺ (ES⁺)

(iii) Benzyl4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzoate

BrettPhos G3 Precatalyst (1.5 g, 1.655 mmol) was added to a degassedmixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 11.82 g, 31.9 mmol), the product from step (ii) above (9.16g, 31.9 mmol) and K₂CO₃ (8.81 g, 63.8 mmol) in DMF (150 mL). The mixturewas heated at 85° C. for 3 h. The reaction was cooled and partitionedbetween EtOAc (400 mL) and water (400 mL). The organic layer was washedwith water (2×400 mL) and brine (400 mL), then dried (MgSO₄), filteredand concentrated in vacuo, affording a brown foam. The crude product waspurified by chromatography on silica gel (220 g column, 20-50%EtOAc/isohexane) to afford the sub-title compound (17.7 g) as an orangefoam.

LCMS m/z 622 (M+H)⁺ (ES⁺)

(iv) Benzyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzoate

TFA (22 mL, 286 mmol) was added to a solution of the product from step(iv) above (17.7 g, 28.5 mmol) in DCM (250 mL) and the reaction stirredovernight. The reaction was concentrated in vacuo affording a dark redoil. The oil was dissolved in DCM (300 mL) and washed with sat. aq.NaHCO₃ solution. The aqueous phase was extracted with DCM (100 mL) andthe combined organics were dried via hydrophobic frit and concentratedin vacuo, affording the sub-title compound (14.5 g) as a brown foam.

1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.15-8.17 (m, 1H), 8.10 (d,1H), 7.62-7.64 (m, 1H), 7.44-7.46 (m, 2H), 7.36-7.40 (m, 4H), 7.31-7.33(m, 1H), 7.11 (d, 1H), 7.00 (s, 2H), 6.72 (d, 1H), 6.59 (dd, 1H), 6.07(d, 1H), 5.87 (s, 2H), 5.23 (s, 2H), 3.65 (s, 6H).

LCMS m/z 522 (M+H)⁺ (ES⁺)

(v) Benzyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzoateMethod 1

BrettPhos G3 Precatalyst (200 mg, 0.221 mmol) was added to a degassedmixture ofN-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)-methanesulfonamide(see Example 8(i) above; 2.15 g, 3.78 mmol), the product from step (ii)above (1.3 g, 4.52 mmol) and K₂CO₃ (1.05 g, 7.60 mmol) in DMF (30 mL).The mixture was heated at 85° C. for 2 h then partitioned between EtOAc(300 mL) and 10% brine solution (300 mL). The organic layer wasseparated, washed with water (200 mL), dried (MgSO₄), filtered andevaporated under reduced pressure. The crude product was purified bychromatography on silica gel (120 g column, 0-100% EtOAc/isohexane) toafford the sub-title compound (1.495 g) as a foam.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.15 (d, 1H), 8.13 (d, 1H),7.86 (d, 1H), 7.73-7.69 (m, 1H), 7.63-7.59 (m, 1H), 7.41-7.29 (m, 6H),7.03-7.01 (m, 3H), 6.64 (dd, 1H), 6.14 (d, 1H), 5.22 (s, 2H), 3.81 (s,3H), 3.67 (s, 6H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 820 (M+H)⁺ (ES⁺)

Method 2

Triethylamine (1 mL, 7.17 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 11.2 g, 28.5 mmol) and the product from step (iv)above (14.5 g, 26.7 mmol) in 2-Me-THF (300 mL) at 80° C. and the mixturestirred for 24 h. The reaction was cooled to rt and concentrated invacuo. The crude product was purified by chromatography on the Companion(220 g column, 30-80% EtOAc in hexane) to afford the sub-title compound(18.9 g) as a pink foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.12-8.16 (m, 2H), 7.87 (d,1H), 7.69-7.73 (m, 1H), 7.59-7.63 (m, 1H), 7.36-7.41 (m, 5H), 7.29-7.33(m, 1H), 7.02-7.03 (m, 3H), 6.64 (dd, 1H), 6.14 (d, 1H), 5.23 (s, 2H),3.81 (s, 3H), 3.67 (s, 6H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 820 (M+H)⁺ (ES⁺)

(vii)4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxybenzoicacid Method 1

A mixture of the product from step (iii) above (1.485 g, 1.811 mmol) and5% Pd/C (200 mg) in THF (10 mL) and EtOH (10 mL) was hydrogenated at 4bar (4×10⁵ Pa) for 20 h. A further portion of 5% Pd/C (200 mg) was addedand the mixture hydrogenated at 5 bar (5×10⁵ Pa) for a further 8 h thenat 2 bar (2×10⁵ Pa) for 72 h. The mixture was diluted with 1% NH₃/MeOH(20 mL) and filtered through Celite. The filtrate was evaporated underreduced pressure and the solid triturated with ether, filtered and driedto afford the title compound (1.27 g) as a solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 9.06 (s, 1H), 8.92 (s, 1H),8.30 (d, 1H), 8.10-8.18 (m, 3H), 7.87 (d, 1H), 7.71 (t, 1H), 7.61 (t,1H), 7.38-7.41 (m, 1H), 6.97-7.03 (m, 3H), 6.61-6.62 (m, 1H), 6.12 (s,1H), 3.81 (s, 3H), 3.65 (s, 6H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 730 (M+H)⁺ (ES⁺)

Method 2

A mixture of the product from step (vi) above (18.9 g, 21.21 mmol) andPd/C (5 wt %, 5.0 g, 2.349 mmol) in THF (100 mL) and EtOH (100 mL) washydrogenated at 5 Bar (5×10⁵ Pa) for 20 h. The reaction was filteredthrough Celite, washing with MeOH, and the filtrate concentrated invacuo, affording the title compound (15 g) as a grey solid.

LCMS m/z 730 (M+H)⁺ (ES⁺)

Example 472-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)ethyldihydrogen phosphate

Route 1 (i) Di-tert-butyl(2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)-ethyl)phosphate

HATU (0.788 g, 2.072 mmol) was added to a stirred solution of4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2,6-dimethoxybenzoicacid (see Example 46 above; 1.26 g, 1.727 mmol),2-(2-(2-aminoethoxy)ethoxy)ethyl di-tert-butyl phosphate (see Example19(ii) above; 2.68 mmol) and Hünig's base (0.8 mL, 4.58 mmol) in DMF (20mL). The mixture was stirred for 3 h then a further portion of Hünig'sbase (0.8 mL, 4.58 mmol) and HATU (0.788 g, 2.072 mmol) were added,stirred for 2 h then partitioned between EtOAc (200 mL) and water (150mL). The organic layer was separated, washed with sat aq NaHCO₃ soln(100 mL), brine (100 mL), dried (MgSO₄), filtered and evaporated underreduced pressure. The crude product was purified by chromatography onsilica gel (80 g column, 0-10% MeOH/DCM) to afford the sub-titlecompound (240 mg) as a foam.

¹H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.15 (s, 1H), 9.03 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.14 (d, 1H), 8.12 (d, 1H),7.87 (d, 1H), 7.83 (t, 1H), 7.71 (t, 1H), 7.61 (t, 1H), 7.39 (d, 1H),7.02 (d, 1H), 6.94 (s, 2H), 6.61 (dd, 1H), 6.10 (d, 1H), 3.95-3.91 (m,2H), 3.81 (s, 3H), 3.61 (s, 6H), 3.60-3.57 (m, 2H), 3.54 (s, 4H), 3.44(t, 2H), 3.28-3.23 (m, 2H), 3.10 (s, 3H), 1.40 (s, 18H), 1.27 (s, 9H).

LCMS m/z 1053 (M+H)⁺ (ES⁺); 75% purity @ 254 nm.

(ii)2-(2-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)ethyldihydrogen phosphate

TFA (500 μL, 6.49 mmol) was added to a solution of the product from step(i) above (230 mg, 0.164 mmol) in DCM (5 mL) and the mixture stirred for1 h. The solvent was evaporated and the residue loaded onto a column ofSCX in MeCN. The column was washed with MeOH and then the product waseluted with 0.7 M ammonia in MeOH. The filtrate was concentrated invacuo to afford a foam that was triturated with MeCN, filtered and driedto give a solid. The solid was purified by preparative HPLC (Varian,Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5μm, 19×50 mm column, 20-50% MeCN in Water) to afford the title compoundas the ammonium salt (72 mg) as a colourless solid.

¹H NMR (of ammonium salt; 400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.05 (s,2H), 8.36 (d, 1H), 8.17 (d, 1H), 8.16-8.10 (m, 2H), 7.91-7.82 (m, 2H),7.73-7.65 (m, 1H), 7.64-7.56 (m, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.86(s, 2H), 6.62 (dd, 1H), 6.12 (d, 1H), 3.87-3.73 (m, 5H), 3.57 (s, 6H),3.55-3.49 (m, 6H), 3.44 (t, 2H), 3.25 (q, 2H), 3.09 (s, 3H), 1.27 (s,9H).

LCMS (of ammonium salt) m/z 941 (M+H)⁺ (ES⁺)

Route 2 (A) Dibenzyl(2-(2-(2-(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)-ethyl)phosphate

Dibenzyl diisopropylphosphoramidite (4.00 mL, 11.93 mmol) was addeddropwise to a solution of4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,6-dimethoxybenzamide(see Example 36 above; 5.44 g, 5.94 mmol) and 5-methyl-1H-tetrazole(1.75 g, 20.81 mmol) in a mixture of THF (15 mL) and DMF (45 mL) and themixture stirred at rt for 22 h. The reaction was cooled to 0° C. andH₂O₂ (3.00 mL, 26.4 mmol) added. The reaction was warmed to rt andstirring continued for 1 h. The reaction was partitioned between EtOAc(300 mL) and water (300 mL). The organic phase was washed with saturatedsodium bisulfite solution (150 mL), sat aq. NaHCO₃ solution (150 mL) andbrine (150 mL), then dried (MgSO₄), filtered and concentrated in vacuo,affording a pale yellow foam. The crude product was purified bychromatography on the Companion (220 g column, 1-8% MeOH in DCM) toafford the sub-title compound (5.69 g) as an off-white foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.14 (s, 1H), 9.02 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H), 8.11-8.14 (m, 2H), 7.87 (d,1H), 7.81 (t, 1H), 7.69-7.73 (m, 1H), 7.59-7.63 (m, 1H), 7.33-7.40 (m,11H), 7.03 (d, 1H), 6.94 (s, 2H), 6.61 (dd, 1H), 6.12 (d, 1H), 5.04 (d,4H), 4.05-4.09 (m, 2H), 3.81 (s, 3H), 3.57-3.63 (m, 8H), 3.52 (s, 4H),3.42 (t, 2H), 3.24 (q, 2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS m/z 1121 (M+H)⁺ (ES⁺); 561 (M+2H)²⁺ (ES⁺)

(B)2-(2-(2-(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2,6-dimethoxybenzamido)ethoxy)ethoxy)ethyldihydrogen phosphate Method 1

A solution of sodium bicarbonate (837 mg, 9.96 mmol) in water (30 mL)was added to a mixture of the product from step (A) above (5.69 g, 4.97mmol) and Pd/C (5 wt %, 2.3 g, 1.081 mmol) in MeOH (150 mL) and THF (50mL). The mixture was hydrogenated at 5 Bar (5×10⁵ Pa) over the weekend.Additional Pd/C (500 mg) was added and stirring continued under H₂overnight. Additional Pd/C (700 mg) was added and stirring continuedunder H₂ for 48 h. The reaction was filtered through celite, washingwith MeOH and the filtrate concentrated in vacuo. When most of theorganic solvent had been removed, the remaining aqueous solution wasazeotroped with MeCN. The resulting solid was further dried at 50° C. ina dessicator overnight, affording the title compound, di-sodium salt(4.65 g) as a beige solid.

¹H NMR (of disodium salt; 400 MHz, DMSO-d6) δ: 9.69 (s, 1H), 9.08 (s,1H), 8.92 (s, 1H), 8.43 (d, 1H), 8.13 (d, 2H), 7.88 (t, 1H), 7.83 (d,1H), 7.64-7.70 (m, 2H), 7.56-7.60 (m, 1H), 7.35 (d, 1H), 7.03 (d, 1H),6.82 (s, 2H), 6.63 (d, 1H), 6.13 (d, 1H), 3.79 (s, 3H), 3.73 (m, 2H),3.54 (s, 6H), 3.42-3.50 (m, 8H), 3.25 (q, 2H), 2.70 (s, 3H), 1.23 (s,9H).

LCMS (of disodium salt) m/z 941 (M+H)⁺ (ES⁺)

Method 2

To a mixture of the product from step (A) above (410 mg, 0.366 mmol) andPd/C (5 wt %, 50 mg, 0.023 mmol) in EtOH (6 mL) and THF (3 mL) was addedNaOH (30 mg, 0.750 mmol) in water (3 mL) and the resulting mixturehydrogenated at 5 Bar (5×10⁵ Pa) overnight. The reaction was filteredthrough Celite, washing with MeOH. The filtrate was concentrated invacuo affording an off-white foam. The solid was dissolved in water (1mL) and loaded onto a column of Dowex resin (Na⁺ form, 15 g). Theproduct was eluted with water (25 mL) and the aqueous materiallyophilised affording the title compound, mono-sodium salt (300 mg) as alow density white solid.

¹H NMR (of mono-sodium salt; 400 MHz, DMSO-d6) δ: 9.44 (s, 1H), 9.15 (s,1H), 9.04 (s, 1H), 8.95 (s, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 8.11-8.14(m, 2H), 7.84-7.87 (m, 2H), 7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H), 7.39(d, 1H), 7.03 (d, 1H), 6.92 (s, 2H), 6.61 (dd, 1H), 6.12 (d, 1H), 3.87(q, 2H), 3.81 (s, 3H), 3.60 (s, 6H), 3.53-3.57 (m, 6H), 3.45 (t, 2H),3.26 (q, 2H), 3.10 (s, 3H), 1.27 (s, 9H).

LCMS (of mono-sodium salt) m/z 941 (M+H)⁺ (ES⁺)

Example 484-((4-((4-(3-(5-(tert-Butyl)-3-(N-(2-hydroxyethyl)methylsulfonamido)-2-methoxyphenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)-ethyl)benzamide

(i)N-(2-(Benzyloxy)ethyl)-N-(5-(tert-butyl)-2-methoxy-3-nitrophenyl)methanesulfonamide

A mixture ofN-(5-(tert-butyl)-2-methoxy-3-nitrophenyl)methanesulfonamide (0.5 g,1.654 mmol), ((2-bromoethoxy)methyl)benzene (400 mg, 1.860 mmol) andK₂CO₃ (0.457 g, 3.31 mmol) in DMF (8 mL) was stirred at rt for 24 h thenheated at 50° C. for 48 h. The mixture was partitioned between ether (70mL) and water (60 mL), the organic layer washed with brine (50 mL),dried (MgSO₄), filtered and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel (40 g column, 0-30%EtOAc/isohexane) to afford the sub-title compound (618 mg) as a yellowoil.

¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.54 (s, 1H), 7.38-7.26 (m, 5H),4.48 (s, 2H), 3.99 (s, 3H), 3.93 (brs, 2H), 3.52 (t, 2H), 3.14 (s, 3H),1.32 (s, 9H)

(ii)N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)-N-(2-(benzyloxy)ethyl)methanesulfonamide

A mixture of the product from step (i) above (600 mg, 1.375 mmol), Fepowder (800 mg, 14.33 mmol) and NH₄Cl (30 mg, 0.561 mmol) in THF (15 mL)and water (5 mL) was heated at 70° C. for 2 h. The mixture was filteredthrough celite and the residue partioned between EtOAc (50 mL) and sataq NaHCO₃ soln (40 mL). The organic layer was washed with brine (40 mL),dried (MgSO₄), filtered and evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel (40 g column, 0-35%EtOAc/isohexane) to afford the sub-title compound (425 mg) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.38-7.29 (m, 5H), 7.03 (s, 1H), 6.81 (s, 1H),4.51 (s, 2H), 3.98 (s, 3H), 3.98-3.87 (br m, 2H), 3.49 (t, 2H), 3.16 (s,3H), 1.28 (s, 9H).

LCMS m/z 407 (M+H)⁺ (ES⁺)

(iii) Phenyl(3-(N-(2-(benzyloxy)ethyl)methylsulfonamido)-5-(tert-butyl)-2-methoxyphenyl)-carbamate

Phenyl chloroformate (141 μL, 1.123 mmol) was added to a mixture of theproduct from step (ii) above (415 mg, 1.021 mmol) and NaHCO₃ (257 mg,3.06 mmol) in DCM (10 mL) and THF (5 mL). The mixture was stirred for 18h then partitioned between DCM (50 mL) and water (50 mL), the organiclayer dried (MgSO₄) and evaporated under reduced pressure to afford thesub-title compound which was used crude in the next step.

(iv) Phenyl(5-(tert-butyl)-3-(N-(2-hydroxyethyl)methylsulfonamido)-2-methoxyphenyl)-carbamate

A mixture of the product from step (iii) above (537 mg, 1.02 mmol) and5% Pd—C (60 mg) in THF (10 mL) was hydrogenated at 2 Bar for 3 days. Themixture was filtered and the filtrate used crude as a solution in thenext step.

LCMS m/z 437 (M+H)⁺ (ES⁺); 435 (M−H)⁻ (ES⁻)

(v)4-((4-((4-(3-(5-(tert-Butyl)-3-(N-(2-hydroxyethyl)methylsulfonamido)-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide

To a stirred solution of the product from step (iv) above (218 mg, 0.499mmol) in THF (5 mL) was added4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxy-N-(2-(1-oxidothiomorpholino)ethyl)benzamide(see Example 32(iii) above; 273 mg, 0.499 mmol) and triethylamine (25μL, 0.179 mmol). The resulting mixture was heated to 60° C. overnight.The mixture was heated at 60° C. for 24 h then evaporated under reducedpressure. The crude product was purified by preparative HPLC (Varian,Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5μm, 19×50 mm column, 20-50% MeCN in Water) to afford a beige solid. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 1-10% MeOH in DCM) to afford the title compound (61 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.26 (s, 1H), 8.92 (s, 1H),8.29-8.32 (m, 2H), 8.12-8.17 (m, 3H), 7.87 (d, 1H), 7.76 (d, 1H),7.69-7.73 (m, 1H), 7.63-7.60 (m, 1H), 7.58 (d, 1H), 7.41 (d, 1H), 7.23(dd, 1H), 7.03 (d, 1H), 6.67 (dd, 1H), 6.15 (d, 1H), 4.90 (t, 1H), 3.91(s, 3H), 3.86 (s, 3H), 3.68 (bs, 2H), 3.47 (q, 2H), 3.39 (q, 2H), 3.23(s, 3H), 2.84-2.97 (m, 4H), 2.68-2.75 (m, 4H), 2.55 (t, 2H), 1.29 (s,9H).

LCMS m/z 888 (M+H)⁺ (ES⁺)

Example 49 Diethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)phosphonate

(i) Diethyl (2-methoxy-4-nitrophenyl)phosphonate

1-Iodo-2-methoxy-4-nitrobenzene (1.00 g, 3.58 mmol) was azeotroped withtoluene (12 mL) then dissolved in fresh toluene (12 mL) before additionof DIPEA (1.878 mL, 10.75 mmol) and diethyl phosphonate (0.600 mL, 4.66mmol). The mixture was degassed under vacuum and back filled withnitrogen three times. XantPhos G3 precatalyst (0.102 g, 0.108 mmol) wasadded and the reaction heated at 100° C. (block temperature), 90° C.(internal temperature), under nitrogen for 2 h. The reaction was cooledand the solvent evaporated to give a brown gum. The crude material waspurified by chromatography on silica gel (12 g column, dry load, 50-100%EtOAc/isohexane, product eluted at 70%) to afford the sub-title compound(549 mg) as a waxy brown solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.02 (dd, 1H), 7.88 (ddd, 1H), 7.79 (dd, 1H),4.23 (m, 4H), 4.04 (s, 3H), 1.38 (td, 6H).

LCMS m/z 290 (M+H)⁺ (ES⁺)

(ii) Diethyl (4-amino-2-methoxyphenyl)phosphonate

A mixture of the product from step (i) above (0.55 g, 1.902 mmol) and 5%Pd/C (50 mg) in EtOH (5 mL) was hydrogenated at 5 Bar (5×10⁵ Pa) for 16h. The mixture was filtered, washed with EtOH (2×2 mL) and the filtratewas evaporated under reduced pressure to afford a green solid. Themixture was re-dissolved in EtOH (10 mL), and 5% Pd/C (50 mg) was addedfollowed by conc. HCl (1 drop) and the mixture was hydrogenated at 5 Bar(5×10⁵ Pa) for 16 h. The mixture was filtered, washed with EtOH (2×2 mL)and the filtrate evaporated under reduced pressure to afford a palebrown gum. The mixture was re-dissolved in EtOH (10 mL), and 5% Pd/C (50mg) was added followed by conc. HCl (1 drop) and the mixture washydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture was filtered,washed with EtOH (2×2 mL) and the filtrate evaporated under reducedpressure to afford a pale brown solid. The crude product was purified bychromatography on silica gel (loaded in DCM, EtOAc/MeOH, 0-20%) tofurnish the sub-title compound (397 mg) as a beige solid. 35 ¹H NMR (400MHz, DMSO-d6) δ: 7.27 (dd, 1H), 6.21 (dd, 1H), 6.16 (ddd, 1H), 5.84 (s,2H), 3.89 (dqt, 4H), 3.71 (s, 3H), 1.19 (t, 6H).

LCMS m/z 260 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-(diethoxyphosphoryl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)-naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 298 mg, 0.804 mmol), the product from step (ii) above (250mg, 0.964 mmol), potassium carbonate (222 mg, 1.607 mmol), and BrettPhosG3 precatalyst (7 mg, 7.89 μmol) were degassed under vacuum, backfilling with nitrogen 3 times. DMF (3 mL) was added and the stirredsuspension was degassed under vacuum, back filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 16 h. The mixture was filtered, washed with DCM (2 mL)and concentrated under reduced pressure. The crude product was purifiedby chromatography on silica (12 g column, dry load, DCM/MeOH 0-10%,product eluted at 6%) to furnish the sub-title compound (340 mg) as apale brown solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.35 (d, 2H), 8.17 (d, 1H), 8.14 (m, 1H),7.83 (m, 1H), 7.61 (m, 3H), 7.51 (dd, 1H), 7.46 (dd, 1H), 7.37 (d, 1H),7.23 (ddd, 1H), 6.67 (dd, 1H), 6.14 (d, 1H), 3.94 (m, 4H), 3.75 (s, 3H),1.53 (s, 9H), 1.20 (t, 6H).

(iv) Diethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)-phosphonate

TFA (221 μL, 2.86 mmol) was added to a solution of the product from step(iii) above (340 mg, 0.573 mmol) in DCM (12 mL) and the mixture stirredat rt for 3 h. Additional TFA (221 μL, 2.86 mmol) was added and themixture was stirred for a further 18 h. The mixture was diluted with DCM(30 mL) and 2M NaOH (20 mL) was added. The phases were separated on aphase separation cartridge and the organics concentrated under reducedpressure to furnish the sub-title compound (330 mg) as a brown oil.

¹H NMR (400 MHz, DMSO-d6) δ: 9.24 (s, 1H), 8.17 (m, 1H), 8.11 (d, 1H),7.63 (m, 1H), 7.46 (m, 4H), 7.23 (m, 1H), 7.11 (d, 1H), 6.72 (d, 1H),6.61 (dd, 1H), 6.09 (d, 1H), 5.84 (s, 2H), 3.94 (m, 4H), 3.73 (s, 3H),1.19 (t, 6H).

(v) Diethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)phosphonate

Triethylamine (0.02 mL, 0.143 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 0.262 g, 0.669 mmol) and the product from step (iv)above (0.33 g, 0.669 mmol) in THF (10 mL) at 65° C. (block temperature).The mixture was stirred for 24 h then the solvent was removed underreduced pressure. The crude material was purified by chromatography onsilica gel (12 g column, dry load, 0-10% MeOH/DCM, product eluted at 5%)to afford a brown solid. The product was further purified bychromatography on a C18 column (24 g column, loaded in DMSO, 25%-100%MeCN: 10 mmol ammonium bicarbonate soln.) to furnish the title compound(170 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.31 (s, 1H), 9.15 (s, 1H),8.92 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H),7.92-7.79 (m, 1H), 7.76-7.67 (m, 1H), 7.62 (ddd, 1H), 7.52-7.42 (m, 2H),7.41 (d, 1H), 7.25 (dt, 1H), 7.02 (d, 1H), 6.67 (dd, 1H), 6.16 (d, 1H),3.94 (dqd, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H),1.20 (t, 6H).

LCMS m/z 793 (M+H)⁺ (ES⁺)

Example 50[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethoxy-phosphinicacid

To a solution of diethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)phosphonate(see Example 49 above; 75 mg, 0.095 mmol) in 1,4-dioxane (1 mL) andwater (0.1 mL) was added sodium hydroxide 50 wt % (15 μL, 0.284 mmol)and the solution was stirred at 50° C. (block temperature) for 24 h.Additional sodium hydroxide 50 wt % (15 μL, 0.284 mmol) was added andthe mixture was stirred for a further 2 days. More sodium hydroxide 50wt % (54 μL) was added and the mixture was stirred for a further 24 h.EtOH (0.5 mL) was added and the mixture was stirred for a further 3days. Acetic acid (27 μL, 0.472 mmol) was added and the mixture wasconcentrated under reduced pressure. The crude product was purified bypreparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic,Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water)to afford the title compound (15 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.57 (s, 1H), 9.03 (d, 2H), 8.32 (d, 1H),8.17 (d, 1H), 8.11 (dd, 2H), 7.91-7.78 (m, 1H), 7.63 (dt, 2H), 7.46 (s,1H), 7.38 (d, 1H), 7.25 (s, 1H), 7.11 (s, 1H), 7.02 (d, 1H), 6.65-6.54(m, 1H), 6.11 (s, 1H), 3.81 (s, 3H), 3.69 (m, 5H), 3.09 (s, 3H), 1.27(s, 9H), 1.06 (t, 3H).

LCMS m/z 765 (M+H)⁺ (ES⁺)

Example 51 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate

(i) Ethyl ethyl(2-methoxy-4-nitrophenyl)phosphinate

1-Iodo-2-methoxy-4-nitrobenzene (1 g, 3.58 mmol), was azeotroped withtoluene (12 mL) then dissolved in fresh toluene (12 mL) before additionof DIPEA (1.878 mL, 10.75 mmol) and ethyl ethylphosphinate (see, forexample, Petnehazy, I. et al., Synth. Commun. 2003, 33, 1665-1674; 0.569g, 4.66 mmol). The mixture was degassed under vacuum and back filledwith nitrogen three times. XantPhos G3 precatalyst (0.102 g, 0.108 mmol)was added and the reaction heated at 100° C. (block temperature), 90° C.(internal temperature), under nitrogen for 2.5 h. The reaction wascooled and the solvent evaporated to give a brown gum. The crudematerial was purified by chromatography on silica gel (12 g column, dryload, 50-100% EtOAc/isohexane, product eluted at 98%) to afford thesub-title compound (0.92 g) as a pale brown solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.17 (dd, 1H), 7.94 (dt, 1H), 7.79 (dd, 1H),4.03 (s, 3H), 3.96 (dddq, 2H), 2.09 (m, 2H), 1.29 (t, 3H), 1.12 (dt,3H).

LCMS m/z 274 (M+H)⁺ (ES⁺)

(ii) Ethyl (4-amino-2-methoxyphenyl)(ethyl)phosphinate

A mixture of the product from step (i) above (0.92 g, 3.37 mmol) and 5%Pd/C (50 mg) in EtOH (10 mL) was hydrogenated at 5 Bar (5×10⁵ Pa) for 16h. The mixture was filtered, washed with EtOH (2×2 mL) and the filtrateevaporated under reduced pressure to afford a pale brown gum. Themixture was re-dissolved in EtOH (10 mL), and 5% Pd/C (50 mg) was addedfollowed by conc. HCl (1 drop) and the mixture was hydrogenated at 5 Bar(5×10⁵ Pa) for 16 h. The mixture was filtered, washed with EtOH (2×2 mL)and the filtrate evaporated under reduced pressure to afford a palebrown gum. The mixture was re-dissolved in EtOH (10 mL), and 5% Pd/C (50mg) was added followed by conc. HCl (1 drop) and the mixture washydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture was filtered,washed with EtOH (2×2 mL) and the filtrate evaporated under reducedpressure to afford a pale brown solid. The crude product was purified bychromatography on silica gel (loaded in DCM, EtOAc/MeOH, 0-20%) tofurnish the sub-title compound (459 mg) as a cream solid.

LCMS m/z 244 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-(ethoxy(ethyl)phosphoryl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 368 mg, 0.994 mmol), the product from step (ii) above (290mg, 1.192 mmol), potassium carbonate (275 mg, 1.987 mmol), and BrettPhosG3 precatalyst (8.8 mg, 9.92 μmol) were degassed under vacuum, backfilling with nitrogen 3 times. DMF (3 mL) was added and the stirredsuspension was degassed under vacuum, back filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 16 h. The mixture was diluted with DCM (20 mL) thenwater (20 mL) was added and the phases separated on a phase separationcartridge. The crude product was purified by chromatography on silica(24 g column, dry load, DCM/MeOH, 0-10%) to give a white solid. Theproduct was further purified by chromatography on silica (24 g column,dry load, PhMe/iPrOH 0-30%, product eluted at 15%) to furnish thesub-title compound (304 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.35 (d, 2H), 8.27-8.06 (m, 2H), 7.90-7.78(m, 1H), 7.68-7.49 (m, 5H), 7.37 (d, 1H), 7.26 (dt, 1H), 6.66 (dd, 1H),6.14 (d, 1H), 3.87-3.72 (m, 4H), 3.65 (ddq, 1H), 1.94-1.78 (m, 2H), 1.53(s, 9H), 1.12 (t, 3H), 0.91 (dt, 3H).

LCMS m/z 578 (M+H)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate

TFA (203 μL, 2.64 mmol) was added to a solution of the product from step(iii) above (305 mg, 0.528 mmol) in DCM (4 mL) and the mixture stirredat rt for 3 h. Additional TFA (203 μL, 2.64 mmol) was added and themixture was stirred for a further 16 h. The solvent was removed underreduced pressure and the residue azeotroped with toluene (5 mL) tofurnish a brown oil. The residue was dissolved in DCM (20 mL) and washedwith 1M NaOH (20 mL). The aqueous was extracted with DCM (20 mL) and thecombined organics were washed with brine (20 mL), dried (MgSO₄) andconcentrated under reduced pressure to furnish the sub-title compound(310 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.13 (s, 1H), 8.11-8.04 (m, 1H), 8.02 (d,1H), 7.56-7.51 (m, 1H), 7.49-7.41 (m, 1H), 7.41-7.33 (m, 3H), 7.21-7.13(m, 2H), 7.12-7.05 (m, 1H), 7.02 (d, 1H), 6.63 (d, 1H), 6.51 (dd, 1H),6.01 (d, 1H), 3.76-3.67 (m, 1H), 3.65 (s, 3H), 3.60-3.50 (m, 1H),1.82-1.70 (m, 2H), 1.02 (td, 3H), 0.81 (dtd, 3H).

LCMS m/z 478 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate

Triethylamine (0.018 mL, 0.130 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 0.255 g, 0.649 mmol) and the product from step (iv)above (0.31 g, 0.649 mmol) in THF (10 mL) at 65° C. (block temperature).The mixture was stirred for 24 h then the solvent was removed underreduced pressure. The crude material was purified by chromatography onsilica gel (12 g column, dry load, 0-10% MeOH/DCM, product eluted at 5%)to afford a beige solid. The product was further purified bychromatography on a C18 column (24 g column, loaded in DMSO, 25%-100%MeCN: 10 mmol ammonium bicarbonate soln.) to furnish the title compound(233 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1H), 9.30 (s, 1H), 8.94 (s, 1H),8.31 (m, 2H), 8.20-8.09 (m, 3H), 7.86 (d, 1H), 7.71 (ddd, 1H), 7.61(ddd, 1H), 7.57-7.47 (m, 2H), 7.40 (d, 1H), 7.27 (dt, 1H), 7.03 (d, 1H),6.66 (dd, 1H), 6.17 (d, 1H), 3.85-3.76 (m, 1H), 3.81 (s, 3H), 3.76 (s,3H), 3.65 (dddd, 1H), 3.10 (s, 3H), 1.92-1.79 (m, 2H), 1.27 (s, 9H),1.11 (t, 3H), 0.90 (dt, 3H).

LCMS m/z 777 (M+H)⁺ (ES⁺)

Example 52[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-ethyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(ethyl)phosphinate(see Example 51 above; 100 mg, 0.129 mmol) in 1,4-dioxane (1.0 mL) andwater (0.1 mL) was added sodium hydroxide 50 wt % (10 μL, 0.189 mmol)and the mixture was stirred at 50° C. (hotplate temperature) for 24 h.Additional sodium hydroxide 50 wt % (9.61 μL, 0.182 mmol) was added andthe mixture was stirred for a further 24 h before more sodium hydroxide50 wt % (74 μL) was added. After a further 24 h, EtOH (0.5 mL) was addedand the mixture was stirred for a further 3 days. Acetic acid (37 μL,0.646 mmol) was added and the mixture was concentrated under reducedpressure. The crude product was purified by preparative HPLC (Waters,Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5μm, 19×50 mm column, 35-65% MeCN in Water) to afford the title compound(23 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.53 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H),8.31 (d, 1H), 8.23-8.06 (m, 3H), 7.90-7.81 (m, 1H), 7.74-7.56 (m, 2H),7.50 (dd, 1H), 7.39 (d, 2H), 7.18 (d, 1H), 7.02 (d, 1H), 6.63 (dd, 1H),6.14 (d, 1H), 3.81 (s, 3H), 3.69 (s, 3H), 3.09 (s, 3H), 1.72 (dq, 2H),1.27 (s, 9H), 0.86 (dt, 3H).

LCMS m/z 749 (M+H)⁺ (ES⁺)

Example 53 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)phosphinate

(i) Ethyl (2-methoxy-4-nitrophenyl)(phenyl)phosphinate

1-Iodo-2-methoxy-4-nitrobenzene (1.00 g, 3.58 mmol), was azeotroped withtoluene (12 mL) then dissolved in fresh toluene (12 mL) before additionof DIPEA (1.9 mL, 10.88 mmol) and ethyl phenylphosphinate (0.79 g, 4.64mmol). The mixture was degassed under vacuum and back filled withnitrogen three times. XantPhos G3 precatalyst (0.10 g, 0.106 mmol) wasadded and the reaction heated at 100° C. (block temperature), 90° C.(internal temperature), under nitrogen for 2.5 h. The reaction wascooled and the solvent evaporated to give a brown gum. The crudematerial was purified by chromatography on silica gel (12 g column, dryload, 50-100% EtOAc/isohexane, product eluted at 70%) to afford thesub-title compound (0.95 g) as a brown, waxy solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.19 (dd, 1H), 7.91 (dt, 1H), 7.85 (m, 2H),7.69 (dd, 1H), 7.55 (m, 1H), 7.46 (m, 2H), 4.14 (dq, 2H), 3.82 (s, 3H),1.39 (t, 3H).

LCMS m/z 322 (M+H)⁺ (ES⁺)

(ii) Ethyl (4-amino-2-methoxyphenyl)(phenyl)phosphinate

A mixture of the product from step (i) above (0.95 g, 2.96 mmol) and 5%Pd/C (50 mg) in EtOH (10 mL) was hydrogenated at 5 Bar (5×10⁵ Pa) for 16h. The mixture was filtered, washed with EtOH (2×2 mL) and the filtrateevaporated under reduced pressure to afford a pale brown gum. Themixture was re-dissolved in EtOH (10 mL) and 5% Pd/C (50 mg) was addedfollowed by conc. HCl (1 drop) and the mixture was hydrogenated at 5 Bar(5×10⁵ Pa) for 16 h. The mixture was filtered, washed with EtOH (2×2 mL)and the filtrate evaporated under reduced pressure to afford a palebrown gum. The mixture was re-dissolved in EtOH (10 mL), and 5% Pd/C (50mg) was added followed by conc. HCl (1 drop) and the mixture washydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture was filtered,washed with EtOH (2×2 mL) and the filtrate evaporated under reducedpressure to afford a pale brown solid. The crude product was purified bychromatography on silica gel (loaded in DCM, EtOAc/MeOH, 0-20%) tofurnish the sub-title compound (446 mg) as an orange solid.

¹H NMR (400 MHz, DMSO-d6) δ: 7.70 (m, 2H), 7.52-7.41 (m, 4H), 6.22 (dt,1H), 6.15 (dd, 1H), 5.85 (s, 2H), 3.86 (m, 2H), 3.59 (s, 3H), 1.22 (t,3H).

LCMS m/z 292 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-(ethoxy(phenyl)phosphoryl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 279 mg, 0.752 mmol), the product from step (ii) above (263mg, 0.903 mmol), potassium carbonate (208 mg, 1.505 mmol), and BrettPhosG3 precatalyst (6.7 mg, 7.55 μmol) were degassed under vacuum, backfilling with nitrogen 3 times. DMF (3 mL) was added and the stirredsuspension was degassed under vacuum, back filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 16 h. The mixture was filtered, washed with DCM (2 mL)and concentrated under reduced pressure. The crude product was purifiedby chromatography on silica (12 g column, dry load, DCM/MeOH 0-10%,product eluted at 6%) to give a beige solid. The product was furtherpurified by chromatography on silica (24 g column, dry load, PhMe/iPrOH0-30%, product eluted at 11%) to furnish the sub-title compound (324 mg)as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.36 (d, 2H), 8.23-8.02 (m, 2H), 7.91-7.78(m, 1H), 7.75-7.67 (m, 2H), 7.67-7.61 (m, 3H), 7.61-7.56 (m, 1H),7.56-7.50 (m, 1H), 7.48-7.43 (m, 3H), 7.37 (d, 1H), 7.27 (dt, 1H), 6.65(dd, 1H), 6.13 (d, 1H), 3.97-3.81 (m, 2H), 3.62 (s, 3H), 1.52 (s, 9H),1.23 (t, 3H).

LCMS m/z 627 (M+H)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)-phosphinate

TFA (200 μL, 2.60 mmol) was added to a solution of the product from step(iii) above (325 mg, 0.519 mmol) in DCM (4 mL) and the mixture stirredat rt for 3 h. Additional TFA (200 μL, 2.60 mmol) was added and themixture was stirred for a further 16 h. The mixture was diluted with DCM(20 mL) and washed with 1M NaOH (20 mL). The aqueous was extracted withDCM (20 mL) and the combined organics were washed with brine (20 mL),dried (MgSO₄) and concentrated under reduced pressure to furnish thesub-title compound (270 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.15 (s, 1H), 8.13-8.03 (m, 1H), 8.00 (d,1H), 7.70-7.57 (m, 2H), 7.57-7.47 (m, 2H), 7.47-7.40 (m, 1H), 7.40-7.26(m, 5H), 7.17 (dt, 1H), 7.01 (d, 1H), 6.62 (d, 1H), 6.51 (dd, 1H), 6.00(d, 1H), 5.76 (s, 1H), 5.67 (s, 1H), 3.92-3.70 (m, 2H), 3.51 (s, 3H),1.14 (t, 3H).

LCMS m/z 526 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)phosphinate

Triethylamine (0.014 mL, 0.103 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 0.202 g, 0.514 mmol) and the product from step (iv)above (0.27 g, 0.514 mmol) in THF (10 mL) at 65° C. (block temperature).The mixture was stirred for 24 h then the solvent was removed underreduced pressure. The crude material was purified by chromatography onsilica gel (12 g column, dry load, 0-10% MeOH/DCM, product eluted at 5%)to afford a beige solid. The product was further purified bychromatography on a C18 column (24 g column, loaded in DMSO, 25%-100%MeCN: 10 mmol ammonium bicarbonate soln.) to furnish the title compound(181 mg) as a white solid.

LCMS m/z 825 (M+H)⁺ (ES⁺)

Example 54[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-phenyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(phenyl)phosphinate(see Example 53 above; 100 mg, 0.121 mmol) in 1,4-dioxane (1.0 mL) andwater (0.1 mL) was added sodium hydroxide 50 wt % (10 μL, 0.189 mmol)and the mixture was stirred at 50° C. (hotplate temperature) for 24 h.Additional sodium hydroxide 50 wt % (10 μL, 0.189 mmol) was added andthe mixture was stirred for a further 24 h before more sodium hydroxide50 wt % (74 μL) was added. After a further 24 h, EtOH (0.5 mL) was addedand the mixture was stirred for a further 3 days. Acetic acid (100 μL,1.747 mmol) was added and the mixture was concentrated under reducedpressure. The crude product was purified by preparative HPLC (Waters,Basic (0.1% Ammonium Bicarbonate), Waters X-Bridge Prep-C18, 5 μm, 19×50mm column, 35-65% MeCN in Water) to afford the title compound (31 mg) asa white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.70 (s, 1H), 9.09 (d, 2H), 8.37-8.27 (m,1H), 8.15 (d, 1H), 8.10 (d, 1H), 8.07 (d, 1H), 7.83 (dd, 1H), 7.72-7.53(m, 5H), 7.36 (d, 1H), 7.29 (d, 3H), 7.22-7.08 (m, 2H), 7.02 (d, 1H),6.58 (dd, 1H), 6.11 (d, 1H), 3.79 (s, 3H), 3.44 (s, 3H), 3.08 (s, 3H),1.26 (s, 9H).

LCMS m/z 797 (M+H)⁺ (ES⁺)

Example 55 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

(i)N-(5-(tert-Butyl)-2-methoxy-3-nitrophenyl)-N-methylmethanesulfonamide

To a solution ofN-(5-(tert-butyl)-2-methoxy-3-nitrophenyl)methanesulfonamide (see, forexample, Cirillo, P. F. et al., WO 2002/083628, 24 Oct. 2002; 1.51 g,4.99 mmol) in DMF (10 mL) was added potassium carbonate (1.035 g, 7.49mmol) followed by iodomethane (0.468 mL, 7.49 mmol), and the mixture wasstirred at rt for 20 h. The mixture was poured into water (50 mL) andextracted with Et₂O (2×50 mL). The combined organics were washed withwater (50 mL) and brine (50 mL), dried (MgSO₄) and concentrated underreduced pressure. The crude product was purified by chromatography onsilica (24 g column, dry load, iso-hexane/EtOAc 0-100%, to furnish thesub-title compound (1.51 g) as a white solid.

¹H NMR (400 MHz, DMSO) δ: 7.83 (d, 1H), 7.73 (d, 1H), 3.88 (s, 3H), 3.25(s, 3H), 3.17 (s, 3H), 1.31 (s, 9H).

LCMS m/z 317 (M+H)⁺ (ES⁺)

(ii)N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)-N-methylmethanesulfonamide

A mixture of the product from step (i) above (1.5 g, 4.74 mmol) and 5%Pd/C (5 g, Type 39, 58% w/w paste with water) in EtOAc (10 mL) and EtOH(5 mL) was hydrogenated at 5 bar (5×10⁵ Pa) for 16 h. The mixture wasfiltered through celite washing with EtOAc (3×25 mL) then evaporatedunder reduced pressure to give a beige solid. The residue was slurriedin ether/isohexane (1:1, 300 mL), filtered and washed with isohexane (50mL) to afford the sub-title compound (1.25 g) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 6.73 (d, 1H), 6.51 (d, 1H), 4.96 (s, 2H),3.69 (s, 3H), 3.15 (s, 3H), 3.07 (s, 3H), 1.22 (s, 9H).

LCMS m/z 287 (M+H)⁺ (ES⁺)

(iii) Phenyl(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)carbamate

Phenyl chloroformate (0.55 mL, 4.38 mmol) was added dropwise over 10 minto a stirred solution of the product from step (ii) above (1.25 g, 4.36mmol) and NaHCO₃ (0.733 g, 8.73 mmol) in THF (5 mL) and DCM (15 mL) atrt. The mixture was stirred overnight, then diluted with DCM (50 mL),washed with water (50 mL) and brine (50 mL), then dried (MgSO₄) andevaporated to give a solid. The product was slurried withcyclohexane/ether (1:1, 10 mL), filtered, washed with isohexane (3×5 mL)and dried at 40° C. under vacuum to give the sub-title compound (1.65 g)as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 7.83-7.61 (m, 1H), 7.44 (dd,2H), 7.31-7.20 (m, 3H), 7.17 (d, 1H), 3.85 (s, 3H), 3.22 (s, 3H), 3.12(s, 3H), 1.27 (s, 9H).

LCMS m/z 429 (M+Na)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

Triethylamine (10 μL, 0.072 mmol) was added to a solution of the productfrom step (iii) above (152 mg, 0.373 mmol) and ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 43(iv) above; 160 mg, 0.345 mmol) in THF (10 mL) at 65° C.(block temperature), and the mixture was stirred for 24 h. The solventwas removed under reduced pressure and the product was purified bychromatography on a 018 column (40 g column, loaded in DMSO, 25%-100%MeCN: 10 mmol ammonium bicarbonate soln.) to furnish the title compound(107 mg) as a white solid.

LCMS m/z 777 (M+H)⁺ (ES⁺)

Example 56[4-[[4-[[4-[[5-tert-Butyl-2-methoxy-3-[methyl(methylsulfonyl)amino]phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(N-methylmethylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 55 above; 85 mg, 0.110 mmol) in 1,4-dioxane (1.0 mL) andwater (0.1 mL) was added sodium hydroxide 50 wt % (10 μL, 0.193 mmol)and the mixture was stirred at 50° C. (hotplate temperature) for 24 h.Further sodium hydroxide 50 wt % (10 μL, 0.189 mmol) was added and themixture was stirred for 2 days. The mixture was cooled to rt, aceticacid (18 μL, 0.314 mmol) was added, the solvent was removed underreduced pressure and the residue azeotroped with toluene (2 mL). Thecrude product was purified by preparative HPLC (Waters, Basic (0.1%Ammonium Bicarbonate), Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,35-65% MeCN in Water) to afford the title compound (13 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 9.19 (s, 1H), 9.09 (s, 1H),8.35 (d, 1H), 8.30 (d, 1H), 8.11 (dd, 2H), 7.83 (dd, 1H), 7.66-7.55 (m,2H), 7.51 (t, 1H), 7.37 (d, 1H), 7.27 (s, 1H), 7.12 (d, 1H), 7.01 (d,1H), 6.61 (dd, 1H), 6.10 (d, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 3.24 (s,3H), 3.13 (s, 3H), 1.34 (d, 3H), 1.28 (s, 9H).

LCMS m/z 749 (M+H)⁺ (ES⁺)

Example 57 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

Triethylamine (5 μL, 0.036 mmol) was added to a warm solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)carbamate (see, forexample, Fyfe, M. C. T. et. al., WO 2014/162126, 9 Oct. 2014; 60 mg,0.168 mmol) and ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 43(iv) above; 82 mg, 0.168 mmol) in THF (2 mL) at 75° C.(block temperature, internal temp. 60-65° C.), and the mixture stirredfor 16 h. The solvent was evaporated and the residue purified bychromatography on silica gel (12 g column, 2-8% MeOH/DCM) to afford thetitle compound (90 mg) as a colourless solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.48 (s, 1H), 9.30 (s, 1H), 8.89 (s, 1H),8.44 (d, 1H), 8.31 (d, 1H), 8.24-8.13 (m, 2H), 8.10 (d, 1H), 7.87 (d,1H), 7.77-7.67 (m, 1H), 7.66-7.58 (m, 1H), 7.58-7.47 (m, 2H), 7.41 (d,1H), 7.27 (dt, 1H), 7.12 (d, 1H), 6.66 (dd, 1H), 6.18 (d, 1H), 3.88-3.72(m, 7H), 3.72-3.55 (m, 1H), 2.82 (d, 3H), 1.56 (d, 3H), 1.28 (s, 9H),1.12 (t, 3H).

LCMS m/z 726 (M+H)⁺ (ES⁺)

Example 58[4-[[4-[[4-[[5-tert-Butyl-2-methoxy-3-(methylcarbamoyl)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 57 above; 90 mg, 0.124 mmol) in 1,4-dioxane (1 mL), water(0.1 mL) and EtOH (0.1 mL) was added sodium hydroxide 50 wt % (19.64 μL,0.372 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (0.5 mL) and stirred for a further 24 h. Aftercooling to rt, acetic acid (35.5 μL, 0.620 mmol) was added then themixture was concentrated under reduced pressure and azeotroped withtoluene (2 mL). The crude product was purified by preparative HPLC(Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-BridgePrep-C18, 5 μm, 19×50 mm column, 35-65% MeCN in Water) to afford thetitle compound (53 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H), 9.11 (s, 2H), 8.42 (d, 1H),8.35 (d, 1H), 8.16 (d, 1H), 8.14-8.03 (m, 2H), 7.71-7.55 (m, 2H), 7.50(dd, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 7.17-7.06 (m, 2H), 6.61 (dd, 1H),6.12 (d, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 2.81 (d, 3H), 1.35 (d, 3H),1.28 (s, 9H).

LCMS m/z 699 (M+H)⁺ (ES⁺)

Example 59 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate

(i) Ethyl methyl(2-methyl-4-nitrophenyl)phosphinate

To a solution of ethyl methylphosphinate (see, for example, Chebib, M.et al., WO 2006/000043, 5 Jan. 2006; 504 mg, 4.66 mmol) in toluene (6mL) were added 1-iodo-2-methyl-4-nitrobenzene (944 mg, 3.59 mmol) andDIPEA (1.9 mL, 10.88 mmol). The mixture was degassed under vacuum andback filled with nitrogen three times. XantPhos G3 precatalyst (102 mg,0.108 mmol) was added, and the mixture was degassed three more times,then heated at 100° C. (block temperature) under nitrogen for 90 min.The reaction was cooled and the solvent evaporated to give a brown gum.The crude material was purified by chromatography on silica gel (12 gcolumn, dry load, 50-100% EtOAc/isohexane, product eluted at 98%) toafford a pale brown solid. The residue was taken up in DCM (10 mL),washed with 1M HCl (10 mL) and concentrated to give a brown oil. Thecrude material was re-purified by chromatography on silica gel (12 gcolumn, dry load, 0-10% DCM/MeOH) to afford the sub-title compound (578mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ: 8.19 (m, 2H), 8.05 (dd, 1H), 4.01 (ddq,1H), 3.87 (ddq, 1H), 2.68 (m, 3H), 1.75 (d, 3H), 1.25 (t, 3H).

LCMS m/z 244 (M+H)⁺ (ES⁺)

(ii) Ethyl (4-amino-2-methylphenyl)(methyl)phosphinate

A mixture of the product from step (i) above (575 mg, 2.364 mmol) andPd/C (252 mg, 0.118 mmol) (Type 87L) in EtOH (6 mL, 103 mmol) and HCl (1drop) was hydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture wasfiltered, washed with EtOH (2×5 mL) and water (5 mL), then the solventwas removed under reduced pressure to furnish the sub-title compound(490 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ: 7.62-7.28 (m, 1H), 6.56-6.39 (m, 2H), 3.86(dp, 1H), 3.79-3.65 (m, 1H), 2.36 (s, 3H), 1.54 (d, 3H), 1.20 (t, 3H).

LCMS m/z 214 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-(ethoxy(methyl)phosphoryl)-3-methylphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 937 mg, 2.53 mmol), the product from step (ii) above (490mg, 2.298 mmol), potassium carbonate (635 mg, 4.60 mmol) and BrettPhosG3 precatalyst (20 mg, 0.023 mmol) were degassed under vacuum, backfilling with nitrogen 3 times. DMF (5 mL) was added and the stirredsuspension was degassed under vacuum, back filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 20 h. The mixture was diluted with water (50 mL) andextracted with DCM/IPA (10:1, 2×25 mL). The combined organics werewashed with water (2×50 mL), dried (MgSO₄) and concentrated underreduced pressure to give a brown oil. The crude product was purified bychromatography on silica (24 g column, dry load, PhMe/IPA 0-30%, producteluted at 12%) to furnish the sub-title compound (0.79 g) as a pale pinksolid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 9.22 (s, 1H), 8.23-8.05 (m,2H), 7.84 (dd, 1H), 7.68-7.54 (m, 3H), 7.52-7.43 (m, 1H), 7.37 (d, 1H),7.31-7.10 (m, 2H), 6.65 (dd, 1H), 6.13 (d, 1H), 3.95-3.69 (m, 2H), 2.43(d, 3H), 1.58 (d, 3H), 1.53 (s, 9H), 1.20 (t, 3H).

LCMS m/z 548 (M+H)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate

TFA (550 μL, 7.14 mmol) was added to a solution of the product from step(iii) above (790 mg, 1.443 mmol) in DCM (3.6 mL) and the mixture stirredat rt for 16 h. Additional TFA (550 μL, 7.14 mmol) was added and themixture was stirred for a further 4 h. The mixture was diluted with DCM(20 mL) and washed with 2M NaOH (10 mL). The aqueous was extracted withDCM (20 mL) and the combined organics were washed with water (20 mL) andbrine (20 mL), dried (MgSO₄) and concentrated under reduced pressure tofurnish the sub-title compound (603 mg).

¹H NMR (400 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.11-8.03 (m, 1H), 8.00 (d,1H), 7.61-7.46 (m, 2H), 7.46-7.37 (m, 3H), 7.35 (d, 1H), 7.06 (d, 1H),6.70 (d, 1H), 6.55 (dd, 1H), 6.04 (d, 1H), 3.80 (dp, 1H), 3.73-3.60 (m,1H), 2.34 (d, 3H), 1.50 (d, 3H), 1.12 (t, 3H).

LCMS m/z 448 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate

Triethylamine (11 μL, 0.079 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 144 mg, 0.367 mmol) and the product from step (iv)above (150 mg, 0.335 mmol) in 2-Me-THF (2.5 mL) at 75° C. and themixture stirred for 16 h. Additional triethylamine (11 μL, 0.079 mmol)was added and stirring continued overnight. The solution was cooled tort and concentrated in vacuo onto silica gel. The crude product waspurified by chromatography on the Companion (12 g column, 1-6% MeOH inDCM) to afford the title compound (187 mg) as a pale pink solid.

LCMS m/z 746 (M+H)⁺ (ES⁺)

Example 60[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-naphthyl]oxy]-2-pyridyl]amino]-2-methyl-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methylphenyl)(methyl)phosphinate(see Example 59 above; 187 mg, 0.251 mmol) in 1,4-dioxane (2 mL), water(0.2 mL) and EtOH (0.2 mL) was added sodium hydroxide 50 wt % (40 μL,0.758 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (1 mL), cooled to rt and acetic acid (72 μL, 1.258mmol) was added. The mixture was concentrated under reduced pressure andazeotroped with toluene (2 mL) to give a white solid. The crude productwas purified by preparative HPLC (Waters, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,35-65% MeCN in Water) to afford an off-white solid. The resulting solidwas slurried in hot MeCN (2 mL) and decanted to give the title compound(5 mg) as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1H), 9.13 (d, 2H), 8.92 (s, 1H),8.30 (d, 1H), 8.19 (d, 1H), 8.16-8.09 (m, 2H), 7.87 (dd, 1H), 7.71 (ddd,1H), 7.64-7.50 (m, 3H), 7.44 (s, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.62(dd, 1H), 6.14 (d, 1H), 3.81 (s, 3H), 3.10 (s, 3H), 2.46 (s, 3H), 1.46(d, 3H), 1.27 (s, 9H).

LCMS m/z 719 (M+H)⁺ (ES⁺)

Example 61 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate

(i) 2-Ethoxy-1-iodo-4-nitrobenzene

To a mixture of 2-iodo-5-nitrophenol (500 mg, 1.887 mmol) and potassiumcarbonate (1.3 g, 9.41 mmol) in DMF (6 mL) and water (0.6 mL) was addediodoethane (0.23 mL, 2.86 mmol) and the mixture was heated at 65° C.(block temperature) for 3 h. After cooling to rt, the mixture wasdiluted with water (50 mL) and extracted with EtOAc (2×25 mL). Thecombined organics were washed with water (3×25 mL) and brine (25 mL),dried (MgSO₄) and concentrated under reduced pressure to give a yellowsolid (0.54 g). The crude product was purified by chromatography onsilica gel (12 g column, loaded in DCM, iso-hexane/EtOAc, gradient0-50%, product eluted at 12%) to furnish the sub-title compound (0.54 g)as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ: 7.96 (dd, 1H), 7.58 (m, 2H), 4.20 (q, 2H),1.55 (t, 3H).

(ii) Ethyl (2-ethoxy-4-nitrophenyl)(methyl)phosphinate

To a solution of ethyl methylphosphinate (see, for example, Chebib, M.et al., WO 2006/000043, 5 Jan. 2006; 257 mg, 2.378 mmol) in toluene (3mL) were added the product from step (i) above (540 mg, 1.843 mmol) andDIPEA (0.96 mL, 5.50 mmol). The mixture was degassed under vacuum andback filled with nitrogen three times. XantPhos G3 precatalyst (52 mg,0.055 mmol) was added, and the mixture was degassed three more times.The reaction was heated at 100° C. (block temperature) under nitrogenfor 2 h. The reaction was cooled and the solvent evaporated to give abrown gum. The resulting gum was dissolved in DCM (30 mL), 1M HCl (20mL) was added and the phases were separated. The crude material waspurified by chromatography on silica gel (12 g column, dry load, 50-100%EtOAc/isohexane, product eluted at 98%) to afford the sub-title compound(363 mg) as a yellow gum.

¹H NMR (400 MHz, DMSO-d6) δ: 8.02 (dd, 1H), 7.92 (dt, 1H), 7.84 (dd,1H), 4.29 (qd, 2H), 3.92 (ddq, 1H), 3.72 (ddq, 1H), 1.73 (d, 3H), 1.40(t, 3H), 1.17 (t, 3H).

LCMS m/z 274 (M+H)⁺ (ES⁺)

(iii) Ethyl (4-amino-2-ethoxyphenyl)(methyl)phosphinate

A mixture of the product from step (ii) above (0.36 g, 1.318 mmol) andPd/C (0.140 g, 0.066 mmol) (Type 87L) in EtOH (6 mL, 103 mmol) washydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture was filtered,washed with EtOH (2×5 mL) and water (5 mL), then the solvent was removedunder reduced pressure to give the sub-title compound (326 mg) as ayellow oil.

¹H NMR (400 MHz, DMSO-d6) δ: 7.45-7.31 (m, 1H), 6.32-6.17 (m, 2H), 3.98(dddd, 2H), 3.81-3.70 (m, 1H), 3.61 (ddq, 1H), 1.54 (d, 3H), 1.33 (t,3H), 1.12 (t, 3H).

LCMS m/z 244 (M+H)⁺ (ES⁺)

(iv) tert-Butyl(4-((2-((3-ethoxy-4-(ethoxy(methyl)phosphoryl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 545 mg, 1.470 mmol), the product from step (iii) above (325mg, 1.336 mmol), potassium carbonate (369 mg, 2.67 mmol), and BrettPhosG3 precatalyst (12 mg, 0.014 mmol) were degassed under vacuum, backfilling with nitrogen 3 times. DMF (4 mL) was added and the stirredsuspension was degassed under vacuum, back filling with nitrogen 3times. The reaction was then heated under nitrogen at 85° C. (blocktemperature) for 20 h. The mixture was diluted with water (50 mL) andextracted with DCM/IPA (10:1, 2×25 mL). The combined organics werewashed with water (2×50 mL), dried (MgSO₄) and concentrated underreduced pressure to give a brown oil. The crude product was purified bychromatography on silica (12 g column, dry load, DCM/MeOH 0-10%, producteluted at 6%) to furnish the sub-title compound (0.54 g) as a red solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.30 (s, 1H), 8.21-8.09 (m,1H), 7.89-7.78 (m, 1H), 7.69-7.45 (m, 5H), 7.37 (d, 1H), 7.29-7.11 (m,2H), 6.66 (dd, 1H), 6.13 (d, 1H), 4.09-3.92 (m, 2H), 3.90-3.50 (m, 2H),1.58 (d, 3H), 1.53 (s, 9H), 1.35 (t, 3H), 1.12 (t, 3H).

LCMS m/z 578 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate

TFA (360 μL, 4.67 mmol) was added to a solution of the product from step(iv) above (540 mg, 0.935 mmol) in DCM (2.3 mL) and the mixture stirredat rt for 16 h. Additional TFA (360 μL, 4.67 mmol) was added and themixture was stirred for a further 4 h. The mixture was diluted with DCM(20 mL) and washed with 2M NaOH (10 mL). The aqueous was extracted withDCM (20 mL) and the combined organics were washed with water (20 mL) andbrine (20 mL), dried (MgSO₄) and concentrated under reduced pressure tofurnish the sub-title compound (346 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.11 (s, 1H), 8.12-8.04 (m, 1H), 8.01 (d,1H), 7.54 (dt, 1H), 7.43 (dd, 1H), 7.40-7.33 (m, 3H), 7.12 (dt, 1H),7.02 (d, 1H), 6.62 (d, 1H), 6.51 (dd, 1H), 6.00 (d, 1H), 3.91 (qd, 2H),3.69 (ddt, 1H), 3.53 (ddq, 1H), 1.49 (d, 3H), 1.25 (t, 3H), 1.03 (t,3H).

LCMS m/z 478 (M+H)⁺ (ES⁺)

(vi) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate

Triethylamine (10 μL, 0.072 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 126 mg, 0.321 mmol) and the product from step (v)above (140 mg, 0.293 mmol) in 2-Me-THF (2.5 mL) at 75° C. and themixture stirred for 16 h. The reaction was cooled to rt and concentratedin vacuo onto silica gel. The crude product was purified bychromatography on the Companion (12 g column, 1-7% MeOH in DCM) toafford the title compound (158 mg) as a pink solid.

LCMS m/z 776 (M+H)⁺ (ES⁺)

Example 62[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-ethoxy-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-ethoxyphenyl)(methyl)-phosphinate(see Example 61 above; 158 mg, 0.204 mmol) in 1,4-dioxane (2 mL), water(0.2 mL) and EtOH (0.2 mL) was added sodium hydroxide 50 wt % (32.3 μL,0.611 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (0.5 mL), cooled to rt and acetic acid (58.3 μL,1.018 mmol) was added. The mixture was concentrated under reducedpressure and azeotroped with toluene (2 mL) to give an off white solid.The crude product was purified by preparative HPLC (Waters, Basic (0.1%Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mmcolumn, 35-65% MeCN in Water) to afford a pale pink solid. The resultingsolid was slurried in hot MeCN (2 mL) and decanted to give the titlecompound (5 mg) as a pale pink solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 9.17 (s, 2H), 8.97 (s, 1H),8.31 (d, 1H), 8.18 (d, 1H), 8.16-8.07 (m, 2H), 7.69 (t, 1H), 7.61 (dd,1H), 7.50 (dd, 1H), 7.39 (d, 2H), 7.17 (d, 1H), 7.02 (d, 1H), 6.64 (dd,1H), 6.13 (d, 1H), 3.97 (q, 2H), 3.81 (s, 3H), 3.10 (s, 3H), 1.47 (d,3H), 1.34 (t, 3H), 1.27 (s, 9H).

LCMS m/z 749 (M+H)⁺ (ES⁺)

Example 63 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

(i) tert-Butyl(4-((2-((4-(ethoxy(methyl)phosphoryl)-3-methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et. al, WO2010/067130, 17 Jun. 2010; 372 mg, 1.000 mmol), ethyl(4-amino-2-methoxyphenyl)(methyl)phosphinate (see Example 43(ii) above;275 mg, 1.201 mmol) and p-TSA monohydrate (38.1 mg, 0.200 mmol) in THF(5 mL) was heated at 50° C. (block temperature, 45° C. internaltemperature) for 2 days. After 46 h, further p-TSA monohydrate (38.1 mg,0.200 mmol) was added and the mixture was stirred for a further 5 days.The mixture was cooled then partitioned between EtOAc (50 mL) and 1M HCl(50 mL). The organic layer was washed with brine (50 mL), dried (MgSO₄),filtered and evaporated under reduced pressure to give a pale brownsolid. The crude product was purified by chromatography on silica gel(12 g column, dry load PhMe/IPA 0-30%) to give a pale brown solid. Theproduct was further purified by chromatography on silica gel (24 gcolumn, dry load DCM/MeOH 0-10%, product eluted at 5%) to give thesub-title compound (382 mg) as a beige solid.

LCMS m/z 565 (M+H)⁺ (ES⁺)

(ii) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)-(methyl)phosphinate

TFA (259 μL, 3.37 mmol) was added to a solution of the product from step(i) above (380 mg, 0.673 mmol) in DCM (1.65 mL) and the mixture wasstirred at rt for 3 h. Additional TFA (259 μL, 3.37 mmol) was added andthe mixture was stirred for a further 16 h. More TFA (259 μL, 3.37 mmol)was added and the mixture was stirred for a further 4 h. The mixture wasdiluted with DCM (20 mL) and washed with 2M NaOH (10 mL). The aqueouswas extracted with DCM (20 mL) and the combined organics were washedwith water (20 mL) and brine (20 mL), dried (MgSO₄) and concentratedunder reduced pressure to furnish the sub-title compound (254 mg) as abeige solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.71 (s, 1H), 8.32 (d, 1H), 8.16-7.97 (m,1H), 7.62-7.47 (m, 1H), 7.41-7.19 (m, 4H), 7.08 (d, 1H), 7.04 (d, 1H),6.61 (d, 1H), 6.44 (d, 1H), 5.72 (s, 2H), 3.68 (ddq, 1H), 3.51 (ddq,1H), 3.24 (s, 3H), 1.44 (d, 3H), 1.01 (t, 3H).

LCMS m/z 465 (M+H)⁺ (ES⁺)

(iii) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

Triethylamine (7 μL, 0.050 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 93 mg, 0.237 mmol) and the product from step (ii)above (100 mg, 0.215 mmol) in 2-Me-THF (2.5 mL) at 75° C. and themixture stirred for 16 h. Additional phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (25 mg)was added and heating continued for 24 h. Additional phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (40 mg)was added and heating continued overnight. The resulting solid wasfiltered off and washed with 2-Me-THF (50 mL). The filtrate wasconcentrated in vacuo onto silica gel. The crude product was purified bychromatography on the Companion (12 g column, 1-5% MeOH in DCM) toafford the title compound (97 mg) as a pink glass.

LCMS m/z 763 (M+H)⁺ (ES⁺)

Example 64[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]pyrimidin-2-yl]amino]-2-methoxy-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 63 above; 97 mg, 0.127 mmol) in 1,4-dioxane (1 mL), water(0.1 mL) and EtOH (0.1 mL) was added sodium hydroxide 50 wt % (20 μL,0.379 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (0.5 mL), cooled to rt and acetic acid (36 μL,0.629 mmol) was added. The mixture was concentrated under reducedpressure and azeotroped with toluene (2 mL) to give a white solid. Thecrude product was purified by preparative HPLC (Waters, Basic (0.1%Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mmcolumn, 35-65% MeCN in Water) to afford a white solid. The resultingsolid was slurried in hot MeCN (2 mL) and decanted to give a pale yellowsolid. The supernatant was concentrated to give a white solid. Bothsolids were found to be 94% pure by LCMS, and so were re-combined andpurified by chromatography on reverse-phase flash C18 chromatography (12g column, 25-100% MeCN/Water 0.1% Formic Acid) to afford the titlecompound (18 mg).

¹H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H), 9.54 (s, 1H), 9.13 (s, 1H),9.02 (s, 1H), 8.47 (d, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.09 (d, 1H),7.83 (d, 1H), 7.58 (m, 2H), 7.40 (d, 1H), 7.25 (m, 2H), 7.02 (d, 2H),6.68 (d, 1H), 3.81 (s, 3H), 3.45 (s, 3H), 3.09 (s, 3H), 1.42 (d, 3H),1.26 (s, 9H).

LCMS m/z 736 (M+H)⁺ (ES⁺)

Example 65 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)phosphinate

(i) Ethyl (2-chloro-4-nitrophenyl)(methyl)phosphinate

To a solution of ethyl methylphosphinate (see, for example, Chebib, M.et al., WO 2006/000043, 5 Jan. 2006; 530 mg, 4.90 mmol) in toluene (5mL) were added 2-chloro-1-iodo-4-nitrobenzene (835 mg, 2.95 mmol) andDIPEA (1.5 mL, 8.59 mmol). The mixture was degassed under vacuum andback filled with nitrogen three times. XantPhos G3 precatalyst (84 mg,0.088 mmol) was added, and the mixture was degassed three more times.The reaction was heated at 100° C. (block temperature) under nitrogenfor 1 h. The reaction was cooled and the solvent evaporated to give abrown gum. The resulting gum was dissolved in DCM (30 mL), 1M HCL (20mL) was added and the phases were separated. The organic phase was dried(MgSO₄) and concentrated under reduced pressure. The crude material waspurified by chromatography on silica gel (12 g column, dry load, 50-100%EtOAc/isohexane, product eluted at 98%) to afford the sub-title compound(519 mg) as a brown solid.

¹H NMR (400 MHz, DMSO-d6) δ: 8.40 (dd, 1H), 8.35 (ddd, 1H), 8.23 (dd,1H), 4.00 (ddq, 1H), 3.83 (ddq, 1H), 1.85 (d, 3H), 1.23 (t, 3H).

LCMS m/z 264 (M+H)⁺ (ES⁺)

(ii) Ethyl (4-amino-2-chlorophenyl)(methyl)phosphinate

The product from step (i) above (200 mg, 0.759 mmol) was dissolved inEtOH (5 mL) and iron powder (425 mg, 7.61 mmol) was added followed by asolution of NH₄Cl (61 mg, 1.140 mmol) in water (1 mL). The resultingsuspension was heated at 80° C. for 2 h. The reaction was cooled to rtand filtered through celite. The filtrate was concentrated in vacuoaffording a dark brown solid. The material was partitioned between water(5 mL) and EtOAc (5 mL). The aqueous phase was extracted with EtOAc (2mL) and the combined organic phases were washed with brine (5 mL), dried(MgSO₄), filtered and concentrated in vacuo affording the sub-titlecompound (148 mg) as a pale brown oil.

¹H NMR (400 Hz, DMSO-d6) δ: 7.57 (dd, 1H), 6.66 (dd, 1H), 6.57 (dt, 1H),6.08 (s, 2H), 3.79-3.89 (m, 1H), 3.63-3.73 (m, 1H), 1.64 (d, 3H), 1.18(t, 3H).

LCMS m/z 234 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((3-chloro-4-(ethoxy(methyl)phosphoryl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 140 mg, 0.377 mmol) and the product from step (ii) above (80mg, 0.342 mmol), were stirred in DMF (2 mL) at 45° C. until anhomogeneous solution was obtained. Freshly ground potassium carbonate(142 mg, 1.027 mmol), was added and the mixture degassed under vacuum,back filling with nitrogen 3 times. BrettPhos G3 precatalyst (10 mg,0.011 mmol) was added and the stirred suspension was heated undernitrogen at 75° C. (internal temperature) for 1 h. Additional BrettPhosG3 precatalyst was added (5 mg) and heating continued for 2 h. Thereaction was cooled to rt and filtered. The filtrate was concentrated invacuo onto silica gel. The crude product was purified by chromatographyon the Companion (12 g column, 1-5% MeOH in DCM) to afford the sub-titlecompound (194 mg) as a beige glass.

LCMS m/z 568 (M+H)⁺ (ES⁺)

(iv) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)-phosphinate

TFA (250 μL, 3.24 mmol) was added to a solution of the product from step(iii) above (194 mg, 0.342 mmol) in DCM (2 mL) and the mixture stirredat rt for 16 h. The reaction was concentrated in vacuo affording a brownoil. The oil was re-dissolved in DCM (5 mL) and partitioned with sat.aq. NaHCO₃ solution (10 mL). The aqueous phase was extracted with DCM(2×1 mL) and the combined organics dried via hydrophobic frit thenconcentrated in vacuo affording the sub-title compound (158 mg) as apale beige foam.

1H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 8.14-8.18 (m, 2H), 8.09 (dd,1H), 7.75 (dd, 1H), 7.62-7.64 (m, 1H), 7.51 (d, 1H), 7.43-7.48 (m, 2H),7.12 (d, 1H), 6.72 (d, 1H), 6.67 (dd, 1H), 6.09 (d, 1H), 5.86 (s, 2H),3.83-3.92 (m, 1H), 3.66-3.76 (m, 1H), 1.69 (d, 3H), 1.19 (t, 3H).

LCMS m/z 468 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)phosphinate

Triethylamine (10 μL, 0.072 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 128 mg, 0.326 mmol) and the product from step (iv)above (140 mg, 0.299 mmol) in 2-Me-THF (2.5 mL) at 75° C. and themixture stirred for 16 h. The reaction was cooled to rt, filteredthrough celite and the filtrate concentrated in vacuo onto silica gel.The crude product was purified by chromatography on the Companion (12 gcolumn, 1-7% MeOH in DCM) to afford the title compound (176 mg) as apink solid.

LCMS m/z 766 (M+H)⁺ (ES⁺)

Example 66[[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-chloro-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-chlorophenyl)(methyl)phosphinate(see Example 65 above; 176 mg, 0.230 mmol) in 1,4-dioxane (2 mL), water(0.2 mL) and EtOH (0.2 mL) was added sodium hydroxide 50 wt % (36 μL,0.682 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (1 mL), cooled to rt and acetic acid (66 μL, 1.153mmol) was added. The mixture was concentrated under reduced pressure andazeotroped with toluene (2 mL) to give a white solid. The crude productwas purified by preparative HPLC (Waters, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,35-65% MeCN in Water) to afford the title compound (66 mg) as a whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1H), 9.23 (s, 1H), 9.14 (s, 1H),8.35 (d, 1H), 8.20-8.07 (m, 3H), 7.90 (d, 1H), 7.83 (dd, 1H), 7.73 (dd,1H), 7.65-7.54 (m, 2H), 7.37 (t, 2H), 7.02 (d, 1H), 6.65 (dd, 1H), 6.09(d, 1H), 3.81 (s, 3H), 3.08 (s, 3H), 1.37 (d, 3H), 1.27 (s, 9H).

LCMS m/z 739 (M+H)⁺ (ES⁺)

Example 67 Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)(methyl)phosphinate

(i) Ethyl (2-fluoro-4-nitrophenyl)(methyl)phosphinate

To a solution of ethyl methylphosphinate (see, for example, Chebib, M.et al., WO 2006/000043, 5 Jan. 2006; 356 mg, 3.30 mmol) in toluene (6mL) were added 2-fluoro-1-iodo-4-nitrobenzene (880 mg, 3.30 mmol) andDIPEA (1.7 mL, 9.73 mmol). The mixture was degassed under vacuum andback filled with nitrogen three times. XantPhos G3 precatalyst (94 mg,0.099 mmol) was added and the reaction heated at 100° C. (blocktemperature) under nitrogen for 90 min. The reaction was cooled and thesolvent evaporated to give a brown gum. The crude material was purifiedby chromatography on silica gel (12 g column, dry load, 50-100%EtOAc/isohexane, product eluted at 98%) to afford a pale brown solid.The residue was taken up in DCM (10 mL), washed with 1M HCl (10 mL) andconcentrated to give a brown oil. The crude material was purified bychromatography on silica gel (12 g column, dry load, 0-10% DCM/MeOH) toafford the sub-title compound (514 mg) as a yellow oil.

¹H NMR (400 MHz, DMSO-d6) δ: 8.25 (m, 2H), 8.08 (m, 1H), 4.02 (ddq, 1H),3.85 (ddq, 1H), 1.80 (dd, 3H), 1.21 (t, 3H).

LCMS m/z 248 (M+H)⁺ (ES⁺)

(ii) Ethyl (2-(dimethylamino)-4-nitrophenyl)(methyl)phosphinate

To a stirred solution of the product from step (i) above (200 mg, 0.809mmol) and dimethylamine hydrochloride (132 mg, 1.618 mmol) in DMF (1mL), in a sealed tube, was added triethylamine (280 μL, 2.009 mmol) andthe mixture heated to 70° C. for 2h. The reaction was cooled to rt,diluted with MeOH (5 mL) and concentrated in vacuo to dryness. Theresidue was re-dissolved in MeOH and loaded onto a pre-conditionedcartridge of SCX resin. The resin was washed with MeOH then the productreleased with 1% NH₃ in MeOH. The ammonia solution was concentrated invacuo affording the sub-title compound (147 mg) as a yellow oil.

LCMS m/z 273 (M+H)⁺ (ES⁺)

(iii) Ethyl (4-amino-2-(dimethylamino)phenyl)(methyl)phosphinate

5% Pd/C (50 mg, 0.023 mmol) was added to a solution of the product fromstep (ii) above 147 mg, 0.491 mmol) in EtOH (5 mL). The reaction wasstirred under hydrogen for 2 h. The catalyst was filtered off and thesolvent evaporated to give the sub-title compound (117 mg) as a paleyellow solid

¹H NMR (400 MHz, DMSO-d6) δ: 7.42 (dd, 1H), 6.52 (dd, 1H), 6.37 (d, 1H),5.69 (bs, 2H), 3.86-3.96 (m, 1H), 3.72-3.81 (m, 1H), 2.58 (s, 6H), 1.61(d, 3H), 1.21 (t, 3H).

LCMS m/z 243 (M+H)⁺ (ES⁺)

(iv) tert-Butyl(4-((2-((3-(dimethylamino)-4-(ethoxy(methyl)phosphoryl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 140 mg, 0.377 mmol) and the product from step (iii) above(100 mg, 0.343 mmol), were stirred in DMF (2 mL) at 45° C. until anhomogeneous solution was obtained. Freshly ground potassium carbonate(142 mg, 1.028 mmol) was added and the mixture degassed under vacuum,back filling with nitrogen 3 times. BrettPhos G3 precatalyst (10 mg,0.011 mmol) was added and the stirred suspension was heated undernitrogen at 75° C. (internal temperature) for 1 h. The mixture wascooled to room temperature, filtered and the solvent evaporated to givea dark oil. The residue was dissolved in DCM and pre-absorbed ontosilica gel. The crude product was purified by chromatography on theCompanion (12 g column, 1-5% MeOH in DCM) to afford the sub-titlecompound (196 mg) as a pale tan solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.26 (s, 1H), 8.13-8.187 (m,2H), 7.83 (d, 1H), 7.55-7.66 (m, 5H), 7.50 (d, 1H), 7.39 (d, 1H), 6.65(d, 1H), 6.12 (s, 1H), 3.88-3.99 (m, 1H), 3.74-3.85 (m, 1H), 2.58 (s,6H), 1.66 (d, 3H), 1.53 (s, 9H), 1.22 (t, 3H)

LCMS m/z 577 (M+H)⁺ (ES⁺)

(v) Ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)-(methyl)phosphinate

TFA (250 μL, 3.24 mmol) was added to a solution of the product from step(iv) above (95 mg, 0.135 mmol) in DCM (2 mL) and the mixture stirred atrt for 16 h. The reaction was concentrated in vacuo affording a brownoil. The oil was re-dissolved in DCM (5 mL) and partitioned with sat.aq. NaHCO₃ solution (10 mL). The aqueous phase was extracted with DCM(2×1 mL) and the combined organics dried via hydrophobic frit thenconcentrated in vacuo affording the sub-title compound (74 mg) as a palebeige foam.

LCMS m/z 477 (M+H)⁺ (ES⁺)

(vi) Ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)(methyl)phosphinate

Triethylamine (5 μL, 0.036 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 67 mg, 0.171 mmol) and the product from step (v)above (74 mg, 0.155 mmol) in 2-Me-THF (1.5 mL) at 75° C. and the mixturestirred for 16 h. The reaction was cooled to rt and concentrated invacuo onto silica gel. The crude product was purified by chromatographyon the Companion (12 g column, 1-7% MeOH in DCM) to afford the titlecompound (90 mg) as a pale yellow solid.

LCMS m/z 775 (M+H)⁺ (ES⁺)

Example 68[4-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(dimethylamino)phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-(dimethylamino)phenyl)(methyl)phosphinate(see Example 67 above; 90 mg, 0.116 mmol) in 1,4-dioxane (1 mL), water(0.1 mL) and EtOH (0.1 mL) was added sodium hydroxide 50 wt % (18 μL,0.341 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (0.5 mL), cooled to rt and acetic acid (33 μL,0.576 mmol) was added. The mixture was concentrated under reducedpressure and azeotroped with toluene (2 mL) to give a white solid. Thecrude product was purified by preparative HPLC (Waters, Basic (0.1%Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mmcolumn, 35-65% MeCN in Water) to afford the title compound (43 mg) as awhite solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 9.26 (s, 1H), 8.95 (s, 1H),8.31 (d, 1H), 8.21-8.14 (m, 2H), 8.12 (d, 1H), 7.86 (dd, 1H), 7.80 (dd,1H), 7.69 (ddd, 1H), 7.64-7.45 (m, 3H), 7.40 (d, 1H), 7.03 (d, 1H), 6.65(dd, 1H), 6.14 (d, 1H), 3.81 (s, 3H), 3.10 (s, 3H), 2.76 (s, 6H), 1.40(d, 3H), 1.27 (s, 9H).

LCMS m/z 748 (M+H)⁺ (ES⁺)

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ: 9.53 (s, 1H), 8.82 (s, 1H),8.75 (s, 1H), 8.35 (d, 1H), 8.15-7.98 (m, 2H), 7.83 (dd, 1H), 7.74-7.47(m, 4H), 7.35 (d, 1H), 7.19 (d, 1H), 7.13 (dd, 1H), 7.03 (d, 1H), 6.54(dd, 1H), 6.07 (d, 1H), 3.78 (s, 3H), 2.68 (s, 6H), 2.60 (s, 3H), 1.22(s, 9H), 1.18 (d, 3H).

LCMS (of sodium salt) m/z 747 (M+H)⁺ (ES⁺)

Example 69 Ethyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)phosphinate

(i) Ethyl 2-methoxy-4-nitrobenzyl(methyl)phosphinate

1-(Bromomethyl)-2-methoxy-4-nitrobenzene (240 mg, 0.975 mmol) anddiethyl methylphosphonite (200 mg, 1.469 mmol) were heated at 140° C.under a stream of nitrogen for 1 h. The reaction mixture was cooled to50° C. and diluted with CHCl₃ (2 mL) then cooled further to 0° C. beforeaddition of 5 N HCl (1 mL). The reaction mixture was stirred for 15 minthen diluted with water (5 mL) and extracted with CHCl₃ (3×20 mL). Theorganics were bulked and partitioned with 2 N NaOH (10 mL). The organicswere separated, dried (MgSO₄), filtered and the solvent evaporated togive the sub-title compound (270 mg) as a brown oil.

¹H NMR (400 MHz, DMSO-d6) δ: 7.90 (ddd, 1H), 7.83 (d, 1H), 7.58 (dd,1H), 4.09-3.93 (m, 5H), 3.36 (d, 2H), 1.41 (d, 3H), 1.25 (t, 3H).

(ii) Ethyl 4-amino-2-methoxybenzyl(methyl)phosphinate

A mixture of the product from step (i) above (270 mg, 0.988 mmol) and 5%Pd/C J&M type 87L 50% w/w H₂O (100 mg, 0.023 mmol) in EtOH (2 mL) washydrogenated at 5 Bar (5×10⁵ Pa) for 16 h. The mixture was filtered andthe filtrate evaporated under reduced pressure to afford a brown oil.The crude product was loaded onto a column of SCX (10 g) in MeOH. Thecolumn was washed with MeOH and then the product was eluted with 0.7 Mammonia in MeOH. The resultant mixture was concentrated in vacuo toafford the sub-title compound (190 mg) as a brown oil.

¹H NMR (400 MHz, DMSO-d6) δ: 6.83 (dd, 1H), 6.22 (dd, 1H), 6.11 (ddd,1H), 5.03 (s, 2H), 3.91 (pd, 2H), 3.69 (s, 3H), 2.91 (dq, 2H), 1.25-1.15(m, 6H).

LCMS m/z 244 (M+H)⁺ (ES⁺)

(iii) tert-Butyl(4-((2-((4-((ethoxy(methyl)phosphoryl)methyl)-3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

A mixture of tert-butyl(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example1(i) above; 168 mg, 0.452 mmol) and the product from step (ii) above(100 mg, 0.411 mmol), were stirred in DMF (2 mL) at 45° C. until anhomogeneous solution was obtained. Freshly ground potassium carbonate(170 mg, 1.233 mmol), was added and the mixture degassed under vacuum,back filling with nitrogen 3 times. BrettPhos G3 precatalyst (10 mg,0.011 mmol) was added and the stirred suspension was heated undernitrogen at 75° C. (internal temperature) for 1 h. The mixture wascooled to rt and filtered and the solvent evaporated to give a dark oil.The residue was dissolved in DCM and pre-absorbed onto silica gel. Thecrude product was purified by chromatography on the Companion (12 gcolumn, 1-5% MeOH in DCM) to afford the sub-title compound (229 mg) as ayellow oil.

LCMS m/z 578 (M+H)⁺ (ES⁺)

(iv) Ethyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)-phosphinate

TFA (500 μL, 6.49 mmol) was added to a solution of the product from step(iii) above (229 mg, 0.396 mmol) in DCM (2 mL) and the mixture stirredat rt for 2 h. The reaction was concentrated in vacuo affording a brownoil. The oil was re-dissolved in DCM (5 mL) and partitioned with sat.aq. NaHCO₃ solution (10 mL). The aqueous phase was extracted with DCM(2×1 mL) and the combined organics dried via hydrophobic frit thenconcentrated in vacuo affording the sub-title compound (172 mg) as apale brown foam.

¹H NMR (400 MHz, DMSO-d6) δ: 9.31 (bs, 1H), 8.16-8.18 (m, 1H), 8.01 (d,1H), 7.62-7.65 (m, 1H), 7.45-7.50 (m, 2H), 7.16 (s, 1H), 7.13 (d, 1H),7.08 (d, 1H), 6.98 (d, 1H), 6.73 (d, 1H), 6.64 (d, 1H), 6.08 (s, 1H),3.92 (quint, 2H), 3.68 (s, 3H), 2.96-3.10 (m, 2H), 1.24 (d, 3H), 1.18(t, 3H).

LCMS m/z 478 (M+H)⁺ (ES⁺)

(v) Ethyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)phosphinate

Triethylamine (7 μL, 0.050 mmol) was added to a solution of phenyl(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (seeExample 1(iv) above; 90 mg, 0.229 mmol) and the product from step (iv)above (100 mg, 0.209 mmol) in 2-Me-THF (2 mL) at 75° C. and the mixturestirred for 24 h. Additional triethylamine (7 μL, 0.050 mmol) was addedand heating continued overnight. The reaction was cooled to rt, filteredand the filtrate concentrated in vacuo onto silica gel. The crudeproduct was purified by chromatography on the Companion (12 g column,1-5% MeOH in DCM) to afford the title compound (85 mg) as a pale beigesolid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 9.14 (s, 1H), 8.91 (s, 2H),8.30 (d, 1H), 8.19 (d, 1H), 8.09-8.12 (m, 2H), 7.87 (d, 1H), 7.69-7.72(m, 1H), 7.63-7.59 (m, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.10 (d, 1H),7.00-7.03 (m, 2H), 6.57 (dd, 1H), 6.09 (d, 1H), 3.91 (quint, 2H), 3.81(s, 3H), 3.70 (s, 3H), 3.10 (s, 3H), 3.00 (dd, 2H), 1.27 (s, 9H), 1.23(d, 3H), 1.17 (s, 3H). LCMS m/z 776 (M+H)⁺ (ES⁺)

Example 70(4-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl)(methyl)phosphinicacid

To a solution of ethyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)-ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzyl(methyl)phosphinate(see Example 69 above; 85 mg, 0.110 mmol) in 1,4-dioxane (1 mL), water(0.1 mL) and EtOH (0.2 mL) was added sodium hydroxide 50 wt % (18 μL,0.341 mmol) and the mixture was heated at 50° C. for 20 h. The mixturewas diluted with EtOH (0.5 mL), cooled to rt and acetic acid (32 μL,0.559 mmol) was added. The mixture was concentrated under reducedpressure and azeotroped with toluene (2 mL) affording a pale orangesolid. The crude product was purified by preparative HPLC (Waters, Basic(0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm,19×50 mm column, 35-65% MeCN in Water) to afford the title compound (56mg) as a tan solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.78 (s, 1H), 9.12 (s, 1H), 8.80 (s, 1H),8.32 (d, 1H), 8.18 (d, 1H), 8.05-8.07 (m, 2H), 7.83 (d, 1H), 7.63-7.67(m, 1H), 7.56-7.59 (m, 1H), 7.36 (d, 1H), 7.16 (s, 1H), 6.99-7.07 (m,2H), 6.87 (d, 1H), 6.55 (dd, 1H), 5.99 (s, 1H), 3.82 (s, 3H), 3.63 (s,3H), 3.08 (s, 3H), 2.77 (d, 2H), 1.26 (s, 9H), 0.97 (d, 3H).

LCMS m/z 748 (M+H)⁺ (ES⁺)

¹H NMR (of sodium salt; 400 MHz, DMSO-d6) δ: 9.99 (s, 1H), 9.03 (s, 1H),8.74 (s, 1H), 8.34 (d, 1H), 8.05 (d, 1H), 8.03 (d, 1H), 7.80 (d, 1H),7.73 (d, 1H), 7.64-7.48 (m, 2H), 7.32 (d, 1H), 7.12 (d, 1H), 7.06 (dd,1H), 7.02 (d, 1H), 6.81 (d, 1H), 6.52 (dd, 1H), 5.95 (d, 1H), 3.80 (s,3H), 3.62 (s, 3H), 2.71 (s, 3H), 2.58 (d, 2H), 1.23 (s, 9H), 0.76 (d,3H).

LCMS (of sodium salt) m/z 748 (M+H)⁺ (ES⁺)

Example 71 Ethyl(4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

(i) Ethyl(4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate

To a solution of phenyl(3-(tert-butyl)-5-(methylsulfonamido)phenyl)carbamate (see, for example,Fyfe, M. C. T. et al., WO 2014/162126, 9 Oct. 2014; 118 mg, 0.326 mmol)and ethyl(4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 43(iv) above; 150 mg, 0.324 mmol) in THF (10 mL) was addedtriethylamine (9 μL, 0.065 mmol) and the mixture was stirred at 65° C.(block temperature) for 40 h. The mixture was heated to reflux andstirred for a further 24 h. After cooling to rt, the mixture wasconcentrated under reduced pressure and purified by chromatography onsilica gel (12 g column, dry load, 0-10% MeOH/DCM, product eluted at 6%)to afford a beige solid. The product was further purified bychromatography on a C18 column (24 g column, loaded in DMSO, 25%-100%MeCN: 10 mmol ammonium bicarbonate soln.) to furnish the title compound(43 mg) as a white solid.

LCMS m/z 733 (M+H)⁺ (ES⁺)

Example 72[4-[[4-[[4-[[3-tert-Butyl-5-(methanesulfonamido)phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]-methyl-phosphinicacid

To a solution of ethyl(4-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxyphenyl)(methyl)phosphinate(see Example 71 above; 43.4 mg, 0.059 mmol) in 1,4-dioxane (0.7 mL),EtOH (0.2 mL) and water (0.1 mL) was added sodium hydroxide 50 wt % (9.4μL, 0.178 mmol) and the solution was heated at 50° C. (blocktemperature) for 24 h. After cooling to rt, acetic acid (23.78 μL, 0.415mmol) was added, the solvent was evaporated under reduced pressure andthe resulting white solid was azeotroped with toluene (2 mL). The crudeproduct was purified by preparative HPLC (Waters, Basic (0.1% AmmoniumBicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μm, 19×50 mm column,35-65% MeCN in Water) to afford a white solid. The resulting solid wasslurried in hot MeCN (2 mL) and decanted to give the title compound (8mg) as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 9.14 (s, 1H), 8.28 (d, 1H),8.14 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.69-7.46 (m, 3H), 7.45-7.28(m, 4H), 7.13 (s, 1H), 6.87 (t, 1H), 6.65 (dd, 1H), 6.06 (s, 1H), 3.68(s, 3H), 3.00 (s, 3H), 1.45 (d, 3H), 1.26 (s, 9H).

Example 73

The following compounds are prepared by methods analogous to thosedescribed above.

(a)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-(trifluoromethyl)benzoicacid

(b)(2R)-2-amino-3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propanoicacid

(c)(2S)-2-amino-3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propanoicacid

(d)(2R)-2-amino-4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butanoicacid

(e)(2S)-2-amino-4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butanoicacid

(f)(2R)-2-amino-5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoicacid

(g)(2S)-2-amino-5-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]pentanoicacid

(h)(2R)-2-amino-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]hexanoicacid

(i)(2R)-2-amino-7-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]heptanoicacid

(j)(2S)-2-amino-7-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]heptanoicacid

(k)(2S)-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]-2-(methylamino)hexanoicacid

(l)(2S)-6-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoyl-amino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]-2-(dimethylamino)-hexanoicacid

(m)(2R)-2-amino-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-5-oxo-pentanoicacid

(n)(2S)-2-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoicacid

(o)(2R)-2-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoicacid

(p)5-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-3-methoxy-pyridine-2-carboxylicacid

(q)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfanyl-benzoicacid

(r)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfinyl-benzoicacid

(s)4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methylsulfonyl-benzoicacid

(t)2-[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-phenyl]aceticacid

(u)2-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butoxy]aceticacid

(v)2-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]butylamino]aceticacid

(w)3-[3-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]propylamino]propanoicacid

(x)4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethylamino]butanoicacid

(y)(2S)-2-amino-3-[4-[[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]methyl]phenyl]-propanoicacid

(z)(2R)-2-amino-3-[4-[[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]methyl]phenyl]-propanoicacid

(aa)(2R)-2-amino-3-[4-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]phenyl]-propanoicacid

(ab)(4S)-4-amino-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-5-oxo-pentanoicacid

(ac)(3S)-3-amino-4-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-4-oxo-butanoicacid

(ad)(2S)-2-amino-6-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-6-oxo-hexanoicacid

(ae)(2R)-2-amino-6-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]-piperazin-1-yl]-6-oxo-hexanoicacid

(af)(2S)-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-2-(methylamino)-5-oxo-pentanoicacid

(ag)(2S)-5-[4-[2-[[4-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-carbamoylamino]-1-naphthyl]oxy]-2-pyridyl]amino]-2-methoxy-benzoyl]amino]ethyl]piperazin-1-yl]-2-(dimethylamino)-5-oxo-pentanoicacid

Biological Testing: Experimental Methods Enzyme Binding Assays(Kinomescan)

Kinase enzyme binding activities of compounds disclosed herein may bedetermined using a proprietary assay which measures active site-directedcompetition binding to an immobilized ligand (Fabian, M. A. et al.,Nature Biotechnol., 2005, 23:329-336). These assays may be conducted byDiscoverX (formerly Ambit; San Diego, Calif.). The percentage inhibitionproduced by incubation with a test compound may be calculated relativeto the non-inhibited control.

Enzyme Inhibition Assays

The enzyme inhibitory activities of compounds disclosed herein aredetermined by FRET using synthetic peptides labelled with both donor andacceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).

p38 MAPKα Enzyme Inhibition

The following two assay variants can be used for determination of p38MAPKα inhibition.

Method 1

The inhibitory activities of test compounds against the p38 MAPKαisoform (MAPK14: Invitrogen) are evaluated indirectly by determining thelevel of activation/phosphorylation of the down-stream molecule,MAPKAP-K2. The p38 MAPKα protein (80 ng/mL, 2.5 μL) is mixed with thetest compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL or 0.004μg/mL) for 2 hr at RT. The mix solution (2.5 μL) of the p38α inactivetarget MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 μM; aphosphorylation target for MAPKAP-K2) is then added, then the kinasereaction is initiated by adding ATP (40 μM, 2.5 μL). The mixture isincubated for 1 hr at RT. Development reagent (protease, 5 μL) is addedfor 1 hr prior to detection in a fluorescence microplate reader(Varioskan® Flash, ThermoFisher Scientific).

Method 2

This method follows the same steps as Method 1 above, but utilises ahigher concentration of the p38 MAPKα protein (2.5 μL of 200 ng/mLprotein instead of 2.5 μL of 80 ng/mL protein) for mixing with the testcompound (tested at either 1 μg/mL, 0.1 μg/mL, 0.01 μg/mL or 0.001μg/mL).

p38 MAPKγ Enzyme Inhibition

The inhibitory activities of compounds of the invention against p38MAPKγ(MAPK12: Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The enzyme (800 ng/mL, 2.5 μL) is incubated withthe test compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or0.004 μg/mL) for 2 hr at RT. The FRET peptides (8 μM, 2.5 μL), andappropriate ATP solution (2.5 μL, 400 μM) are then added to theenzymes/compound mixtures and the whole is incubated for 1 hr.Development reagent (protease, 5 μL) is added for 1 hr prior todetection in a fluorescence microplate reader (Varioskan® Flash, ThermoScientific).

c-Src and Syk Enzyme Inhibition

The inhibitory activities of compounds of the invention against c-Srcand Syk enzymes (Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The relevant enzyme (3000 ng/mL or 2000 ng/mLrespectively, 2.5 μL) is incubated with the test compound (either 1μg/mL, 0.1 μg/mL, 0.01 μg/mL, or 0.001 μg/mL, 2.5 μL each) for 2 hr atRT. The FRET peptides (8 μM, 2.5 μL), and appropriate ATP solutions (2.5μL, 800 μM for c-Src, and 60 μM ATP for Syk) are then added to theenzymes/compound mixtures and the mixture incubated for 1 hr.Development reagent (protease, 5 μL) is added for 1 hr prior todetection in a fluorescence microplate reader (Varioskan® Flash,ThermoFisher Scientific).

GSK 3α Enzyme Inhibition

The following two assay variants can be used for determination of GSK 3αinhibition.

Method 1

The inhibitory activities of compounds of the invention against the GSK3α enzyme isoform (Invitrogen), are evaluated by determining the levelof activation/phosphorylation of the target peptide. The GSK3-α protein(500 ng/mL, 2.5 μL) is mixed with the test compound (2.5 μL at either 4μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRETpeptide (8 μM, 2.5 μL), which is a phosphorylation target for GSK3α, andATP (40 μM, 2.5 μL) are then added to the enzyme/compound mixture andthe resulting mixture incubated for 1 hr. Development reagent (protease,5 μL) is added for 1 hr prior to detection in a fluorescence microplatereader (Varioskan® Flash, ThermoFisher Scientific).

In all cases, the site-specific protease cleaves non-phosphorylatedpeptide only and eliminates the FRET signal. Phosphorylation levels ofeach reaction are calculated using the ratio of coumarin emission(donor) over fluorescein emission (acceptor), for which high ratiosindicate high phosphorylation and low ratios indicate lowphosphorylation levels. The percentage inhibition of each reaction iscalculated relative to non-inhibited control and the 50% inhibitoryconcentration (IC₅₀ value) is then calculated from theconcentration-response curve.

Method 2

This method follows the same steps as Method 1 above, but utilises ashorter period of mixing of the test compound (105 minutes instead of 2hours) with the GSK3-α protein. In addition, the concentrations of testcompound employed are either 10 μg/mL, 1 μg/mL, 0.1 μg/mL, or 0.01 μg/mL

Cellular Assays

The compounds of the invention were studied using one or more of thefollowing assays.

(a) Inhibition of p38 MAPKα and Lck in Jurkat Cells

Jurkat T cells were cultured in starve medium (RPMI 1640+5% FBS) for 24h prior to the experiment. Cells were harvested and resuspended at10×10⁶ cells/mL in starve medium and then plated into round-bottomed 96well plates at 1×10⁶ cells/well. Serial dilutions of test compound wereadded (1% final DMSO concentration) for 2 h prior to stimulation.Following pre-incubation with compound, cells were stimulated with H₂O₂(0.05% final) for 5 min. The reaction was stopped by centrifugation at2000 rpm (3 min, 4° C.), then the supernatant was removed and 100 μL ofcold fix/perm solution (BD Fix/Perm kit #554714) added. Plates wereincubated for 20 min at 4° C. before centrifugation and washing withsupplied ix wash medium (BD Fix/Perm kit #554714). Cells were stainedfor either phospho-p38α (T180/182), supplied by Cell SignallingTechnology (9211s), or phospho-Lck (Y394), supplied by R&D (MAB7500).Antibodies were diluted to 5 μg/mL (R&D) or 1:200 (Cell SignallingTechnology) in wash medium, before being incubated 1 h at 4° C. in thedark. Following 3 repeat washes with ice cold wash buffer, secondaryantibody (anti-rabbit-FITC #F1362 or anti-mouse-FITC #F2883, both fromSigma) was added at a dilution of 1:1000 and incubated for 1 h at 4° C.in the dark. Cells were washed 3× times in cold wash buffer then,following a final wash in cold PBS, were resuspended in 150 μL cold PBS.Cells were analysed by flow cytometry using BD Accuri C6.

(aa) LPS-Induced TNFα/IL-8 Release in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated tomacrophage-type cells by incubation with phorbol myristate acetate (PMA;100 ng/mL) for 48 to 72 hr. Cells are pre-incubated with finalconcentrations of test compound for 2 hr and are then stimulated with0.1 μg/mL of LPS (from E. Coli: 0111:B4, Sigma) for 4 hr. Thesupernatant is collected for determination of TNFα and IL-8concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibitionof TNFα production is calculated as a percentage of that achieved by 10μg/mL of BIRB796 at each concentration of test compound by comparisonagainst vehicle control. The relative 50% effective concentration(REC₅₀) is determined from the resultant concentration-response curve.The inhibition of IL-8 production is calculated at each concentration oftest compound by comparison with vehicle control. The 50% inhibitoryconcentration (IC₅₀) is determined from the resultantconcentration-response curve.

(b) LPS-Induced TNFα/IL-8 Release in PBMC Cells

Peripheral blood mononuclear cells (PBMCs) from healthy subjects areseparated from whole blood using a density gradient (Lymphoprep,Axis-Shield Healthcare). The PBMCs are seeded in 96 well plates andtreated with compounds at the desired concentration for 2 hours beforeaddition of 1 ng/mL LPS (Escherichia Coli 0111:B4 from Sigma Aldrich)for 24 hours under normal tissue culture conditions (37° C., 5% CO₂).The supernatant is harvested for determination of IL-8 and TNFαconcentrations by sandwich ELISA (Duo-set, R&D systems) and read on thefluorescence microplate reader (Varioskan® Flash, ThermoFisherScientific). The concentration at 50% inhibition (IC₅₀) of IL-8 and TNFαproduction is calculated from the dose response curve.

(c) IL-2 and IFN Gamma Release in CD3/CD28 Stimulated PBMC Cells

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells are addedto a 96 well plate pre-coated with a mixture of CD3/CD28 monoclonalantibodies (0.3 μg/mL eBioscience and 3 μg/mL BD Pharmingenrespectively). Compound at the desired concentration is then added tothe wells and the plate left for 3 days under normal tissue cultureconditions. Supernatants are harvested and IL-2 and IFN gamma releasedetermined by Sandwich ELISA (Duo-set, R&D System). The IC₅₀ isdetermined from the dose response curve.

(d) IL-1β-Induced IL-8 Release in HT29 Cells

HT29 cells, a human colon adenocarcinoma cell line, are plated in a 96well plate (24 hr) and pre-treated with compounds at the desiredconcentration for 2 hours before addition of 5 ng/mL of IL-1β (Abcarn)for 24 hours. Supernatants are harvested for IL-8 quantification bySandwich ELISA (Duo-set, R&D System). The IC₅₀ is determined from thedose response curve.

(e) LPS-Induced IL-8 and TNFα Release in Primary Macrophages

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells areincubated for 2 hrs and non-adherent cells removed by washing. Todifferentiate the cells to macrophages, they are incubated with 5 ng/mLof GM-CSF (Peprotech) for 7 days under normal tissue culture conditions.Compounds are then added to the cells at the desired concentration for a2 hour pre-treatment before stimulation with 10 ng/mL LPS for 24 hours.Supernatants are harvested and IL-8 and TNFα release determined bySandwich ELISA (Duo-set, R&D System). The IC₅₀ is determined from thedose response curve.

(f) Poly I:C-Induced ICAM-1 Expression in BEAS2B Cells

Poly I:C is used in these studies as a simple, RNA virus mimic. PolyI:C-Oligofectamine mixture (1 μg/mL Poly I:C, ±2% Oligofectamine, 25 μL;Invivogen Ltd., San Diego, Calif., and Invitrogen, Carlsbad, Calif.,respectively) is transfected into BEAS2B cells (human bronchialepithelial cells, ATCC). Cells are pre-incubated with finalconcentrations of test compounds for 2 hr and the level of ICAM1expression on the cell surface is determined by cell-based ELISA. At atime point 18 hr after poly I:C transfection, cells are fixed with 4%formaldehyde in PBS and then endogenous peroxidase is quenched by theaddition of washing buffer (100 μL, 0.05% Tween in PBS: PBS-Tween)containing 0.1% sodium azide and 1% hydrogen peroxide. Cells are washedwith wash-buffer (3×200 μL) and after blocking the wells with 5% milk inPBS-Tween (100 μL) for 1 hr, the cells are incubated with anti-humanICAM-1 antibody (50 μL; Cell Signalling Technology, Danvers, Mass.) in1% BSA PBS overnight at 4° C.

The cells are washed with PBS-Tween (3×200 μL) and incubated with thesecondary antibody (100 μL; HRP-conjugated anti-rabbit IgG, Dako Ltd.,Glostrup, Denmark). The cells are then incubated with substrate (50 μL)for 2-20 min, followed by the addition of stop solution (50 μL, 1NH₂SO₄). The ICAM-1 signal is detected by reading the absorbance at 450nm against a reference wavelength of 655 nm using a spectrophotometer.The cells are then washed with PBS-Tween (3×200 μL) and total cellnumbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining (50 μL of a 2% solution in PBS) andelution by 1% SDS solution (100 μL) in distilled water. The measured OD450-655 readings are corrected for cell number by dividing with theOD595 reading in each well. The inhibition of ICAM-1 expression iscalculated at each concentration of test compound by comparison withvehicle control. The 50% inhibitory concentration (IC₅₀) is determinedfrom the resultant concentration-response curve.

(g) Cell Mitosis Assay

Peripheral blood mononucleocytes (PBMCs) from healthy subjects areseparated from whole blood (Quintiles, London, UK) using a densitygradient (Histopaque®-1077, Sigma-Aldrich, Poole, UK). The PBMCs (3million cells per sample) are subsequently treated with 2% PHA(phytohaemagglutinin, Sigma-Aldrich, Poole, UK) for 48 hr, followed by a20 hr exposure to varying concentrations of test compounds. At 2 hrbefore collection, PBMCs are treated with demecolcine (0.1 μg/mL;Invitrogen, Paisley, UK) to arrest cells in metaphase. To observemitotic cells, PBMCs are permeabilized and fixed by adding Intraprep (50μL; Beckman Coulter, France), and stained with anti-phospho-histone 3(0.26 ng/L; #9701; Cell Signalling, Danvers, Mass.) and propidium iodide(1 mg/mL; Sigma-Aldrich, Poole, UK) as previously described (MuehlbauerP. A. and Schuler M. J., Mutation Research, 2003, 537:117-130).Fluorescence is observed using an ATTUNE flow cytometer (Invitrogen,Paisley, UK), gating for lymphocytes. The percentage inhibition ofmitosis is calculated for each treatment relative to vehicle (0.5% DMSO)treatment.

(h) Rhinovirus-Induced IL-8 Release and ICAM-1 Expression

Human rhinovirus RV16 is obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks are generated by infecting HeLacells with HRV until 80% of the cells are cytopathic.

BEAS2B cells are infected with HRV at an MOI of 5 and incubated for 2 hrat 33° C. with gentle shaking to promote absorption. The cells are thenwashed with PBS, fresh media added and the cells are incubated for afurther 72 hr. The supernatant is collected for assay of IL-8concentrations using a Duoset ELISA development kit (R&D systems,Minneapolis, Minn.).

The level of ICAM-1 expressing cell surface is determined by cell-basedELISA. At 72 hr after infection, cells are fixed with 4% formaldehyde inPBS. After quenching endogenous peroxidase by adding 0.1% sodium azideand 1% hydrogen peroxide, wells are washed with wash-buffer (0.05% Tweenin PBS: PBS-Tween). After blocking well with 5% milk in PBS-Tween for 1hr, the cells are incubated with anti-human ICAM-1 antibody in 5% BSAPBS-Tween (1:500) overnight. Wells are washed with PBS-Tween andincubated with the secondary antibody (HRP-conjugated anti-rabbit IgG,Dako Ltd.). The ICAM-1 signal is detected by adding substrate andreading at 450 nm with a reference wavelength of 655 nm using aspectrophotometer. The wells are then washed with PBS-Tween and totalcell numbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining and elution with 1% SDS solution. Themeasured OD₄₅₀₋₆₅₅ readings are corrected for cell number by dividingwith the OD₅₉₅ reading in each well. Compounds are added 2 hr before HRVinfection and 2 hr after infection when non-infected HRV is washed out.

(i) Assessment of HRV16 Induced Cytopathic Effect (CPE) in MRC5 Cells

MRC5 cells are infected with HRV16 at an MOI of 1 in DMEM containing 5%FCS and 1.5 mM MgCl₂, followed by incubation for 1 hr at 33° C. topromote adsorption. The supernatants are aspirated, and then fresh mediaadded followed by incubation for 4 days. Where appropriate, cells arepre-incubated with compound or DMSO for 2 hr, and the compounds and DMSOadded again after washout of the virus.

Supernatants are aspirated and incubated with methylene blue solution(100 μL, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2hr at RT. After washing, 1% SDS in distilled water (100 μL) is added toeach well, and the plates are shaken lightly for 1-2 hr prior to readingthe absorbance at 660 nm. The percentage inhibition for each well iscalculated. The IC₅₀ value is calculated from the concentration-responsecurve generated by the serial dilutions of the test compounds.

(j) In Vitro RSV Virus Load in Primary Bronchial Epithelial Cells

Normal human bronchial epithelial cells (NHBEC) grown in 96 well platesare infected with RSV A2 (Strain A2, HPA, Salisbury, UK) at a MOI of0.001 in the LHC8 Media: RPMI-1640 (50:50) containing 15 mM magnesiumchloride and incubated for 1 hr at 37° C. for adsorption. The cells arewashed with PBS (3×200 μL), then fresh media (200 μL) is added andincubation continued for 4 days. Where appropriate, cells arepre-incubated with the compound or DMSO for 2 hr, and then added againafter washout of the virus.

The cells are fixed with 4% formaldehyde in PBS solution (50 μL) for 20min, washed with WB (3×200 μL) (washing buffer, PBS including 0.5% BSAand 0.05% Tween-20) and incubated with blocking solution (5% condensedmilk in PBS) for 1 hr. Cells are then washed with WB (3×200 μL) andincubated for 1 hr at RT with anti-RSV (2F7) F-fusion protein antibody(40 μL; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam) in 5% BSAin PBS-tween. After washing, cells are incubated with an HRP-conjugatedsecondary antibody solution (50 μL) in 5% BSA in PBS-Tween (lot00053170, Cat. No. P0447, Dako) and then TMB substrate added (50 μL;substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems, Inc.).This reaction is stopped by the addition of 2N H₂SO₄ (50 μL) and theresultant signal is determined colourimetrically (OD: 450 nm with areference wavelength of 655 nm) in a microplate reader (Varioskan®Flash, ThermoFisher Scientific).

Cells are then washed and a 2.5% crystal violet solution (50 μL; lot8656, Cat. No. PL7000, Pro-Lab Diagnostics) is applied for 30 min. Afterwashing with WB, 1% SDS in distilled water (100 μL) is added to eachwell, and plates are shaken lightly on the shaker for 1 hr prior toreading the absorbance at 595 nm. The measured OD₄₅₀₋₆₅₅ readings arecorrected to the cell number by dividing the OD₄₅₀₋₆₅₅ by the OD₅₉₅readings. The percentage inhibition for each well is calculated and theIC₅₀ value is calculated from the concentration-response curve generatedfrom the serial dilutions of compound.

(k) Cell Viability Assay: MTT Assay

Differentiated U937 cells are pre-incubated with each test compound(final concentration 1 μg/mL or 10 μg/mL in 200 μL media indicatedbelow) under two protocols: the first for 4 hr in 5% FCS RPM11640 mediaand the second in 10% FCS RPM11640 media for 24 h. The supernatant isreplaced with new media (200 μL) and MTT stock solution (10 μL, 5 mg/mL)is added to each well. After incubation for 1 hr the media are removed,DMSO (200 μL) is added to each well and the plates are shaken lightlyfor 1 hr prior to reading the absorbance at 550 nm. The percentage lossof cell viability is calculated for each well relative to vehicle (0.5%DMSO) treatment. Consequently an apparent increase in cell viability fordrug treatment relative to vehicle is tabulated as a negativepercentage.

(l) Human Biopsy Assay

Intestinal mucosa biopsies are obtained from the inflamed regions of thecolons of IBD patients. The biopsy material is cut into small pieces(2-3 mm) and placed on steel grids in an organ culture chamber at 37° C.in a 5% CO₂/95% O₂ atmosphere in serum-free media. DMSO control or testcompounds at the desired concentration are added to the tissue andincubated for 24 hr in the organ culture chamber. The supernatant isharvested for determination of IL-6, IL-8, IL-1β and TNFα levels by R&DELISA. Percentage inhibition of cytokine release by the test compoundsis calculated relative to the cytokine release determined for the DMSOcontrol (100%).

(m) Accumulation of 13 Catenin in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated intomacrophage-type cells by incubation with PMA (100 ng/mL) for between 48to 72 hr. The cells are then incubated with either final concentrationsof test compound or vehicle for 18 hr. The induction of β-catenin by thetest compounds is stopped by replacing the media with 4% formaldehydesolution. Endogenous peroxide activity is neutralised by incubating withquenching buffer (100 μL, 0.1% sodium azide, 1% H₂O₂ in PBS with 0.05%Tween-20) for 20 min. The cells are washed with washing buffer (200 μL;PBS containing 0.05% Tween-20) and incubated with blocking solution (200μL; 5% milk in PBS) for 1 hr, re-washed with washing buffer (200 μL) andthen incubated overnight with anti-β-catenin antibody solution (50 μL)in 1% BSA/PBS (BD, Oxford, UK).

After washing with washing buffer (3×200 μL; PBS containing 0.05%Tween-20), cells are incubated with a HRP-conjugated secondary antibodysolution (100 μL) in 1% BSA/PBS (Dako, Cambridge, UK) and the resultantsignal is determined colourimetrically (OD: 450 nm with a referencewavelength of 655 nm) using TMB substrate (50 μL; R&D Systems, Abingdon,UK). This reaction is stopped by addition of 1N H₂SO₄ solution (50 μL).Cells are then washed with washing buffer and 2% crystal violet solution(50 μL) is applied for 30 min. After washing with washing buffer (3×200μL), 1% SDS (100 μL) is added to each well and the plates are shakenlightly for 1 hr prior to measuring the absorbance at 595 nm (Varioskan®Flash, Thermo-Fisher Scientific).

The measured OD₄₅₀₋₆₅₅ readings are corrected for cell number bydividing the OD₄₅₀₋₆₅₅ by the OD₅₉₅ readings. The percentage inductionfor each well is calculated relative to vehicle, and the ratio ofinduction normalised in comparison with the induction produced by astandard control comprising the Reference compoundN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide(1 μg/mL), which is defined as unity.

(n) T Cell Proliferation

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). The lymphocytefraction is first enriched for CD4+ T cells by negative magnetic cellsorting as per the manufacturer's instructions (Miltenyi Biotec130-091-155). Naïve CD4+ T cells are then separated using positivemagnetic selection of CD45RA+ cells using microbeads as per themanufacturer's instructions (130-045-901). Cells are plated at 2×10⁵cells per well in 100 μL RPMI/10% FBS on 96 well flat bottomed plate(Corning Costar). 25 μL of test compound are diluted to the appropriateconcentration (8× final concentration) in normal medium and added toduplicate wells on the plate to achieve a dose response range of 0.03ng/mL-250 ng/mL. DMSO is added as a negative control. Plates are allowedto pre-incubate for 2 hours before stimulation with 1 μg/mL anti-CD3(OKT3; eBioscience). After 72 h, the medium in each well is replacedwith 150 μL of fresh medium containing 10 μM BrdU (Roche). After 16 h,the supernatant is removed, the plate is dried and the cells fixed byadding 100 μL of fix/denature solution to each well for 20 min as perthe manufacturer's instructions (Roche). Plates are washed once with PBSbefore addition of the anti-BrdU detection antibody and incubated for 90mins at room temperature. Plates are then washed gently 3× with the washbuffer supplied and developed by addition of 100 μL of substratesolution. The reaction is stopped by addition of 50 μL of 1 M H₂SO₄ andread for absorbance at 450 nm on a plate reader (Varioskan® Flash,ThermoFisher Scientific). The IC₅₀ is determined from the dose responsecurve.

(o) IL-2 and IFNγ release in CD3/CD28 stimulated LPMC cells from IBDpatients

Lamina propria mononuclear cells (LPMCs) are isolated and purified frominflamed IBD mucosa of surgical specimens or from normal mucosa ofsurgical specimens as follows: The mucosa is removed from the deeperlayers of the surgical specimens with a scalpel and cut in fragments ofsize 3-4 mm. The epithelium is removed by washing the tissue fragmentsthree times with 1 mM EDTA (Sigma-Aldrich, Poole, UK) in HBSS(Sigma-Aldrich) with agitation using a magnetic stirrer, discarding thesupernatant after each wash. The sample is subsequently treated withtype 1A collagenase (1 mg/mL; Sigma-Aldrich) for 1 h with stirring at37° C. The resulting cell suspension is then filtered using a 100 μmcell strainer, washed twice, resuspended in RPMI-1640 medium(Sigma-Aldrich) containing 10% fetal calf serum, 100 U/mL penicillin and100 μg/mL streptomycin, and used for cell culture.

Freshly isolated LPMCs (2×10⁵ cells/well) are stimulated with 1 μg/mLα-CD3/α-CD28 for 48 h in the presence of either DMSO control orappropriate concentrations of compound. After 48 h, the supernatant isremoved and assayed for the presence of TNFα and IFNγ by R&D ELISA.Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

(p) Inhibition of Cytokine Release from Myofibroblasts Isolated from IBDPatients

Myofibroblasts from inflamed IBD mucosa are isolated as follows:

The mucosa is dissected and discarded and 1 mm-sized mucosal samples arecultured at 37° C. in a humidified CO₂ incubator in Dulbecco's modifiedEagle's medium (DMEM, Sigma-Aldrich) supplemented with 20% FBS, 1%non-essential amino acids (Invitrogen, Paisley, UK), 100 U/mLpenicillin, 100 μg/mL streptomycin, 50 μg/mL gentamycin, and 1 μg/mLamphotericin (Sigma-Aldrich). Established colonies of myofibroblasts areseeded into 25-cm² culture flasks and cultured in DMEM supplemented with20% FBS and antibiotics to at least passage 4 to provide a sufficientquantity for use in stimulation experiments.

Subconfluent monolayers of myofibroblasts, seeded in 12-well plates at3×10⁵ cells per well, are starved in serum-free medium for 24 h at 37°C., 5% CO₂, before being cultured for 24 h in the presence of eitherDMSO control or appropriate concentrations of compound. After 24 h, thesupernatant is removed and assayed for the presence of IL-8 and IL-6 byR&D ELISA. Percentage inhibition of cytokine release by the testcompounds is calculated relative to the cytokine release determined forthe DMSO control (100%).

(q) Human Neutrophil Degranulation

Neutrophils are isolated from human peripheral blood as follows:

Blood is collected by venepuncture and anti-coagulated by addition of1:1 EDTA:sterile phosphate buffered saline (PBS, no Ca+/Mg+). Dextran(3% w/v) is added (1 part dextran solution to 4 parts blood) and theblood allowed to stand for approximately 20 minutes at rt. Thesupernatant is carefully layered on a density gradient (Lymphoprep,Axis-Shield Healthcare) and centrifuged (15 mins, 2000 rpm, no brake).The supernatant is aspirated off and the cell pellet is re-suspended insterile saline (0.2%) for no longer than 60 seconds (to lysecontaminating red blood cells). 10 times volume of PBS is then added andthe cells centrifuged (5 mins, 1200 rpm). Cells are re-suspended inHBSS+ (Hanks buffered salt solution (without phenol red) containingcytochalasin B (5 μg/mL) and 1 mM CaCl₂) to achieve 5×10⁶ cells/mL.

5×10⁴ cells are added to each well of a V-bottom 96 well plate and areincubated (30 mins, 37° C.) with the appropriate concentration of testcompound (0.3-1000 ng/mL) or vehicle (DMSO, 0.5% final conc).Degranulation is stimulated by addition of fMLP (final concentration 1μM). After a further incubation (30 mins, 37° C.), the cells are removedby centrifugation (5 mins, 1500 rpm) and the supernatants transferred toa flat bottom 96 well plate. An equal volume of tetramethylbenzidine(TMB) is added and, after 10 mins, the reaction terminated by additionof an equal volume of sulphuric acid (0.5 M) and absorbance read at 450nm (background at 655 nm subtracted). The 50% inhibitory concentration(IC₅₀) is determined from the resultant concentration-response curve.

(r) Cell Cytotoxicity Assay

1×10⁵ Jurkat cells (immortalised human T lymphocytes) are added to theappropriate number of wells of a 96 well plate in 100 μL of media (RPMIsupplemented with 10% foetal bovine serum). 1 μL of DMSO control (finalconcentration 1.0% v/v) or test compound (final concentration 20, 5 or 1μg/mL) is added to the wells and incubated at 37° C., 5% CO₂. After 24hours, the plate is centrifuged at 1200 rpm for 3 minutes and thesupernatant discarded. Cells are then resuspended in 150 μL (finalconcentration 7.5 μg/mL) of propidium iodide (PI) in PBS and incubatedat 37° C., 5% CO₂ for 15 minutes. After 15 minutes, cells are analysedby flow cytometry (BD accuri) using the FL3 window. The % viability iscalculated as the % of cells that are PI negative in the test wellsnormalised to the DMSO control.

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity (i)LPS-Induced Neutrophil Accumulation in Mice

Non-fasted Balb/c mice are dosed by the intra tracheal route with eithervehicle, or the test substance at the indicated times (within the range2-8 hr) before stimulation of the inflammatory response by applicationof an LPS challenge. At T=0, mice are placed into an exposure chamberand exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS) for 30 min. Aftera further 8 hr, the animals are anesthetized, their tracheas cannulatedand BALF extracted by infusing and then withdrawing from their lungs 1.0mL of PBS via the tracheal catheter. Total and differential white cellcounts in the BALF samples are measured using a Neubauer haemocytometer.Cytospin smears of the BALF samples are prepared by centrifugation at200 rpm for 5 min at RT and stained using a DiffQuik stain system (DadeBehring). Cells are counted using oil immersion microscopy. Data forneutrophil numbers in BAL are represented as mean±S.E.M. (standard errorof the mean). The percentage inhibition of neutrophil accumulation iscalculated for each treatment relative to vehicle treatment.

(ii) Cigarette Smoke Model

A/J mice (males, 5 weeks old) are exposed to cigarette smoke (4%cigarette smoke, diluted with air) for 30 min/day for 11 days using aTobacco Smoke Inhalation Experiment System for small animals (ModelSIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substances areadministered intra-nasally (35 μL of solution in 50% DMSO/PBS) oncedaily for 3 days after the final cigarette smoke exposure. At 12 hrafter the last dosing, each of the animals is anesthetized, the tracheacannulated and bronchioalveolar lavage fluid (BALF) is collected. Thenumbers of alveolar macrophages and neutrophils are determined by FACSanalysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, Calif.,USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4antibody (neutrophil).

(iii) DSS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle, reference item (5-ASA) or test compoundone day before (Day −1) stimulation of the inflammatory response bytreatment with dextran sodium sulphate (DSS). On Day 0 of the study, DSS(5% w/v) is administered in the drinking water followed by BID dosing ofthe vehicle (5 mL/kg), reference (100 mg/kg) or test compound (5 mg/kg)for 7 days. The drinking water with DSS is replenished every 3 days.During the study, animals are weighed every day and stool observationsare made and recorded as a score, based on stool consistency. At thetime of sacrifice on Day +6, the large intestine is removed and thelength and weight are recorded. Sections of the colon are taken foreither MPO analysis, to determine neutrophil infiltration, or forhistopathology scoring to determine disease severity.

(iv) TNBS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle (5 mL/kg), reference item (Budesonide2.5 mg/kg) or test compound (1 or 5 mg/kg) one day before (Day −1)stimulation of the inflammatory response by treatment with2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol/50%saline). On Day 0 of the study TNBS (200 μL) is administeredintra-colonically via a plastic catheter with BID dosing of the vehicle,reference or test compound continuing for 2 or 4 days. During the study,animals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day 2 (or Day 4), the large intestine is removed and thelength and weight recorded. Sections of the colon are taken forhistopathology scoring to determine disease severity.

(v) Adoptive Transfer in Mice

On Study day 0, female Balb/C mice are terminated and spleens obtainedfor CD45RB^(high) cell isolation (Using SCID IBD cell Separationprotocol). Approximately 4×10⁵ cells/mL CD45RB^(high) cells are theninjected intraperitoneally (100 μL/mouse) into female SCID animals. Onstudy day 14, mice are weighed and randomized into treatment groupsbased on body weight. On Day 14, compounds are administered BID, viaoral gavage, in a dose volume of 5 mL/kg. Treatment continues untilstudy day 42, at which point the animals are necropsied 4 hours afterthe morning administration. The colon length and weight are recorded andused as a secondary endpoint in the study as a measurement of colonoedema. The colon is then divided into six cross-sections, four of whichare used for histopathology scoring (primary endpoint) and two arehomogenised for cytokine analysis. Data shown is the % inhibition of theinduction window between naïve animals and vehicle animals, where higherinhibition implies closer to the non-diseased, naïve, phenotype.

(vi) Endotoxin-Induced Uveitis in Rats

Male, Lewis rats (6-8 weeks old, Charles River UK Limited) are housed incages of 3 at 19-21° C. with a 12 h light/dark cycle (07:00/19:00) andfed a standard diet of rodent chow and water ad libitum. Non-fasted ratsare weighed, individually identified on the tail with a permanentmarker, and receive a single intravitreal administration into the rightvitreous humor (5 μL dose volume) of 100 ng/animal of LPS (Escherichiacoli 0111:B4 prepared in PBS, Sigma Aldrich, UK) using a 32-gaugeneedle. Untreated rats are injected with PBS. Test compound or vehicle(4% polyoxyl 40 stearate, 4% mannitol in PBS (pH 74)) are administeredby the topical route onto the right eye (10 μL) of animals 1 hour priorto LPS, at the time of LPS administration, and 1, 2 and 4 hours post LPSadministration. Before administration, the solution to be administeredis sonicated to ensure a clear solution. 6 hours after LPS dosing,animals are euthanized by overdose with pentobarbitone (via cardiacpuncture). Immediately after euthanasia, 10 μL of aqueous humor iscollected from the right eye of the rats by puncture of the anteriorchamber using a 32 gauge needle under a surgical microscope. The aqueoushumor is diluted in 20 μL of PBS and total cell counts are measuredimmediately using a Countess automated cell counter (Invitrogen).Following collection of the aqueous humour, the right eye of each animalis enucleated and dissected into front (anterior) and back (posterior)sections around the lens. Each section is weighed and homogenised in 500μL of sterile phosphate buffered saline followed by 20 minutescentrifugation at 12000 rpm at 4° C. The resulting supernatant isdivided into 3 aliquots and stored at −80° C. until subsequent cytokineanalysis by R&D DuoSet ELISA.

Summary of In Vitro and In Vivo Screening Results

TABLE 1a Dissociation constants for selected kinases determined byLeadHunter Discover Services (DiscoveRx Corporation, Fremont, CA), usingthe KINOMEscan ™ technology. Test Compound Dissociation Constant (nM)Example No. Lck p38 MAPKα Syk Example 1 4.2 2.8 7.1 Example 2 5.8 23 18Example 44 5.3 1.9 6.6

Studies conducted by LeadHunter Discover Services (DiscoveRxCorporation, Fremont, Calif.) using the KINOMEscan™ technologydetermined that compounds of Example 1, 36, 44 and 47 did not have anysignificant effect on the binding of the kinases B-Raf and B-Raf (V600E)to their standard ligands. Moreover, these compounds showed improvedselectivities compared to the Reference CompoundN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide(WO 2010/112936), as evidenced by lower selectivity scores (Table 1b).

TABLE 1b KinomeScan Selectivity score data at 50 and 500 nM; S(35) =(number of non- mutant kinases with % Ctrl <35)/(number of non-mutantkinases tested); S(10) = (number of non-mutant kinases with % Ctrl<10)/(number of non-mutant kinases tested); S(1) = (number of non-mutantkinases with % Ctrl <1)/(number of non- mutant kinases tested)KinomeScan Selectivity Scores/number of individual kinase hits 50 nM 500nM Compound S(35) S(10) S(1) S(35) S(10) S(1) Reference 0.174/670.083/32 0.018/7 0.370/143 0.272/105 0.117/45 Compound Ex. 1 0.186/750.072/29 0.005/2 0.347/140 0.251/101 0.089/36 Ex. 36 0.149/60 0.050/200.002/1 0.298/120 0.206/83 0.079/32 Ex. 44 0.179/72 0.074/30 0.002/10.337/136 0.241/97 0.102/41 Ex. 47 0.136/55 0.042/17 0.000/0 0.318/1280.223/90 0.074/30

TABLE 1c Results from in vitro p38 MAPKα (Method 2), c-Src, Syk andGSK3α (Method 2) inhibition assays Test Compound IC50 Values for EnzymeInhibition (nM) Example No. p38 MAPKα c-Src Syk GSK3α  1 11 14  5 115  220 20 172 2295  3 — — — 139  4 121  37 277 2015  5 119  31 187 1344  6137  36 315 1900  7 59 21 107 1104  8 214  — — 3767  9 197  316  >1282 4338 10 — — — 5559 11 35 76 318 1303 12 23 209  831 2144 13 — 150  8093634 14 10 19  92 2205 15 64 43 163 2789 16 34 22 107 3727 17(a) — 16 —4003 17(b) 52 20  98 4492 17(c) — — — >11905 17(d) — — — >11905 17(e) —— — 7421 17(f) — — — 1088 17(g) — — — 4096 17(h) — — — 4388 17(i) — — —594 17(j) 21 16  39 2000 17(k) 156  74 336 >11905 17(l) 223  116 389 >12077 17(m) 25 19 192 2771 17(n) — — — >11905 17(o) 232  948 332117(p) 20 21 172 4681 17(q) — — — 1979 17(r) 119  37 102 4045 17(s) — — —394 17(t) — — — 140 17(u) 66 32  86 2247 17(v) 116  43 232 >12107 17(w)— — — 674 17(x) — — — 412 17(y) — — — 5575 17(z) — — — 2876 17(aa) 20 24 61 2933 17(ab) — — — 596 17(ac) — — — 3024 17(ad) — — — 3062 17(ae) 1031 112 3003 17(af)  5 — — 680 17(ag) — 17 105 2745 17(ah) — 20  57 918717(ai) — 14  86 4476 17(aj) — 12  33 2644 17(ak) — 12  85 1818 17(al) —— — 11821 17(am)  4 68 124 — 17(an) — — — — 17(cm) 47 29  82 — 17(cp) —20 393 — 19  8 22  8 — 20 — 77 144 — 21 — 16  15 — 22  6 17 138 — 26 40— — — 36 19 10 190 — 39  6 17 257 — 40 162  195  400 — 41 31 13 325 — 42 3 21  88 — 44 11 20  17 — 45 36 40 108 — 46 — — — 225 47  4 15  8 — 4829 20  55 —

TABLE 2 Inhibition of cytokine release in stimulated cells (assays (b),(c) and (d) above). Test Compound PBMCs Example No. IL-8 IL-2 IFNγ  15.5 1125.5   9.5  2 0.6 101.8  6.2  3 23.7 — 16.7  4 2.3 137.5 11.8  51.5 358.2 10.1  6 2.6 420.2 12.8  7 1.3 220.9  5.8  8 2.9 397.8 10.3  93.0 268.1 20.6 10 6.9 — — 11 1.4 425.8  2.7 12 1.7 860.1  9.9 13 4.71141.5  17.4 14 3.0 221.1 140.5  15 2.2 103.1  7.5 16 1.7 136.4 10.717(a) 3.4 — 16.7 17(b) 1.4  97.7  6.0 17(c) 5.5 — — 17(d) 6.9 — — 17(e)2.1 — — 17(f) 5.8 — — 17(g) 2.8 — — 17(h) 2.0 — — 17(i) 1.4 — — 17(j)1.9  96.0  2.9 17(k) 3.2 446.0 21.7 17(l) 2.1 324.1  6.5 17(m) 2.0 108.611.9 17(n) 4.7 — — 17(o) 3.3 1096.6   3.6 17(p) 3.1 — — 17(q) 4.8 — —17(r) 1.7 153.6  7.0 17(s) 12.0 — — 17(t) 13.1 — — 17(u) 1.7 — — 17(v)3.9 227.2 14.3 17(w) 7.2 — — 17(x) 25.9 — — 17(y) 2.6 — — 17(z) 2.7 —15.3 17(aa) 3.6 144.5 17.2 17(ab) 2.7 — — 17(ac) 2.6 — — 17(ad) 2.8 — —17(ae) 1.7 461.9 18.0 17(af) 1.3 102.6  2.4 17(ag) 1.3 —  5.9 17(ah) 0.8203.5 15.1 17(ai) 1.8 122.0 13.5 17(aj) 1.7 — — 17(ak) 1.7 — — 17(al)6.4 — — 17(am) 2.0 471.6  7.1 17(an) 2.5 — — 17(ao) 1.0 — — 17(ap) 2.6 —— 17(aq) 1.8 — — 17(ar) 88.7 — — 17(as) 15.8 — — 17(at) 14.8 — — 17(au)5.7 — 26.4 17(av) 112.6 — — 17(aw) 78.2 — — 17(ax) 18.2 — — 17(ay) 22.8— 70.2 17(az) 2.1 — — 17(ba) 5.0 — — 17(bb) 1.9 — — 17(bc) 2.9 — —17(bd) 1.6 — — 17(be) 1.1 — — 17(bf) 1.5 — — 17(bg) 2.2 — — 17(bh) 2.1 —— 17(bi) 3.1 — — 17(bj) 76.4 — 313.4  17(bk) 11.3 — — 17(bl) 2.4 — —17(bm) 0.6 — — 17(bn) 0.6 — — 17(bo) 2.2 — — 17(bp) 2.4 — — 17(bq) 1.2 —— 17(br) 14.3 — — 17(bs) 4.8 — — 17(bt) 1.4 — — 17(bu) 45.5 — >1,000   17(bv) 74.5 — — 17(bw) 23.0 — 53.4 17(bx) 7.9 — — 17(by) 0.7 — — 17(bz)12.8 — — 17(ca) 10.3 — — 17(cb) 16.8 — — 17(cc) 211.4 — — 17(cd) 16.8 —— 17(ce) 309.4 — — 17(cf) 22.0 — — 17(cg) 16.2 — 237.1  17(ch) 2.7 — —17(ci) 38.6 — — 17(cj) 3.4 — — 17(ck) 31.7 — — 17(cl) 70.5 — 232.4 17(cm) 1.8 —  2.6 17(cn) 7.6 — — 17(co) 36.7 — — 17(cp) 395.0 — 1084.6 17(cq) 2.3 — — 17(cr) 3.9 — — 17(cs) 23.6 — — 17(ct) 6.9 — — 17(cu) 23.1— — 17(cv) 17.1 — — 17(cw) 53.0 — — 19 149.0 1076.5  160.5  20 2.3 — —21 1.4 — — 22 2.7 — 14.6 23 1.8 — — 24 2.8 — — 25 2.1 — — 26 1.5 — — 274.0 — — 28 0.7 — — 29 2.5 — — 30 7.0 — — 31 2.0 — — 32 1.5 — — 33 8.7 —— 34 2.0 — — 35 52.8 — — 36 1.7 —  8.5 37 5.7 — 14.9 38 1.6 — — 39 5.7 —52.9 40 1.8 — 16.7 41 1.6 — 35.4 42 3.2 — 14.1 43 2.3 — — 44 299.2— >1,000    45 2.4 — — 46 19.6 — — 47 147.1 — 272.3  48 1.1 —  8.4 50445.1 — — 52 348.9 — — 54 478.4 — — 56 >1,000 — — 58 >1,000 — —60 >1,000 — — 62 >1,000 — — 64 >1,000 — — 66 >1,000 — — 68 94.5 — 190.7 70 95.0 — — 72 118.2 — —

As illustrated in Table 3 below, compounds of the examples of thepresent invention are markedly less active than the Reference Compound(N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide;WO 2010/112936) in assay (g) above, which measures impact on celldivision (mitosis) in PBMCs. Similarly, compounds of the examples of thepresent invention are substantially less cytotoxic than the ReferenceCompound, displaying enhanced viabilities in cell cytotoxicity assay (r)above (Table 3).

TABLE 3 Effect of compounds of the examples on cell division in PBMCs(NT = not tested) and on Jurkat cell viability % Inhibition Test ofmitosis % Viability % Viability % Viability compound at 5 μg/mL at 1μg/mL at 5 μg/mL at 20 μg/mL Reference  87.8^(a) 23.5 18.9 17.3 compound 1  2.4 94.4 95.9 95.7  2 48.0 NT NT NT  3 NT 93.4 95.9 91.9  4 46.2 NTNT NT  5 27.7 NT NT NT  6 28.8 NT NT NT  7 59.9 NT NT NT  9 29.8 NT NTNT 11 26.6 NT NT NT 12 22.1 74.5 81.8 82.9 14 60.1 101.9 98.8 0.7 1562.3 99.5 75.0 74.5 16 50.1 90.1 52.5 19.1 17(a) 75.6 NT NT NT 17(b)58.9 102.8 93.8 79.3 17(j) 85.4 NT NT NT 17(k) 24.0 NT NT NT 17(l) 24.9102.8 102.7  102.9 17(m) 80.5 NT NT NT 17(p) 92.0 102.1 49.9 1.5 17(r)36.6 NT NT NT 17(u) 86.9 NT NT NT 17(v) 34.4 NT NT NT 17(x) NT 95.4 94.238.9 17(y) 70.8 NT NT NT 17(z) 69.7 102.9 70.9 2.0 17(aa) 77.7 NT NT NT17(ab) NT 108.6 95.6 93.9 17(ac) 85.8 NT NT NT 17(ad) 93.4 101.4  6.30.4 17(ae) 30.6 93.1 98.5 92.9 17(af) NT 96.7 76.2 54.1 17(ag) 51.8 NTNT NT 17(ah) 32.5 NT NT NT 17(ai) 89.1 NT NT NT 17(aj) 94.9 NT NT NT17(ak) 74.7 99.0 69.5 0.4 17(al) 21.2 NT NT NT 17(am) NT 103.4 90.5 32.517(an) NT 97.9 37.9 1.1 17(ao) NT 89.2 16.5 1.6 17(ap) NT 97.8 40.1 0.617(aq) NT 95.1  0.2 1.3 17(ar) NT 96.1 96.2 95.3 17(at) NT 95.2 93.286.6 17(au) NT 94.0 91.8 80.6 17(ay) NT 95.3 94.6 90.1 17(az) NT 105.493.1 4.5 17(bb) NT 90.9 19.2 0.2 17(bc) NT 93.9 89.2 10.8 17(bd) NT 85.828.7 0.1 17(be) NT 92.4  0.7 0.5 17(bf) NT 90.7  1.5 0.6 17(bg) NT 86.560.0 0.3 17(bh) NT 99.5 67.8 0.6 17(bi) NT 97.4  0.8 0.6 17(bj) NT 96.296.6 94.8 17(bk) NT 93.0 71.8 65.6 17(bl) NT 103.6  0.2 0.5 17(bm) NT103.6  0.2 0.5 17(bn) NT 102.8 65.6 19.5 17(bo) NT 98.5 45.3 14.0 17(bp)NT 93.2 41.0 2.0 17(bq) NT 87.2 55.3 2.0 17(br) NT 91.8 90.7 79.2 17(bs)NT 90.9 48.7 0.3 17(bt) NT 89.8 39.9 22.5 17(bu) NT 92.6 92.6 91.717(bw) NT 94.5 96.2 92.4 17(by) NT 102.4 81.5 1.6 17(bz) NT 93.6 92.764.1 17(ca) NT 92.6 94.0 75.8 17(cd) NT 96.4 96.5 91.4 17(cf) NT 96.796.7 96.8 17(cg) NT 96.1 95.3 92.3 17(ch) NT 82.0 10.2 0.7 17(ck) NT96.1 96.1 95.5 17(cl) NT 93.6 94.0 93.7 17(cm) NT 95.9 77.0 14.5 17(co)NT 94.5 93.3 92.2 17(cp) NT 97.6 96.9 94.7 17(cq) NT 74.3  9.0 0.717(cr) NT 81.1 18.0 0.9 19 NT 105.0 106.0  100.9 20 NT 104.0 99.3 91.821 NT 101.2 82.4 77.1 22 NT 102.8 96.6 42.9 23 NT 92.4 88.9 89.8 24 NT104.3 92.4 9.7 25 NT 91.8 78.9 0.7 26 NT 94.8 84.6 76.6 27 NT 101.2 94.91.7 28 NT 100.0 41.1 18.9 29 NT 101.2 46.6 2.0 31 NT 99.9 97.6 99.0 32NT 95.4 43.1 2.5 33 NT 104.1 95.5 69.3 36 NT 93.3 89.3 84.9 37 NT 52.955.8 28.9 38 NT 90.0 63.7 6.0 39 NT 93.9 87.7 1.5 40 NT 89.6 73.6 67.141 NT 90.5 67.3 55.3 42 NT 96.6 91.7 21.3 44 NT 93.3 90.1 92.2 45 NT97.7 93.7 9.8 47 NT 91.2 96.0 97.8 48 NT 89.0 63.8 54.2 68 NT 95.6 92.790.2 70 NT 95.3 91.9 63.8 ^(a)See, for example, the value reported in WO2013/050757.

As illustrated in Table 4 below, the compound of Example 1 significantlyand dose-dependently reduced cellular infiltration, as revealed bylowered cell counts, and cytokine IL-1β levels in both the anterior andposterior segments of the eyes of rats treated with intravitrealendotoxin LPS (see assay (vi) above).

TABLE 4 Dose-dependent effect of the compound of Example 1 on IL-1βlevels and cell counts in the eyes of LPS-stimulated rats. Data arereported as means ± SEM. IL-1β (pg/mL) IL-1β (pg/mL) Cell countsTreatment n Anterior tissue Posterior tissue (×10⁵/mL) Non-diseased 514.1 ± 6.3 30.8 ± 11.3  1.8 ± 0.2 Vehicle control 8 1636.6 ± 145.1 877.3± 115.6 69.9 ± 5.4 Example 1 8  367.3 ± 100.4 188.1 ± 54.7  21.9 ± 5.0(1 mg/mL) Example 1 8  791.2 ± 131.9 327.4 ± 61.4  30.4 ± 6.7 (0.1mg/mL) Example 1 8  980.0 ± 110.8 740.5 ± 56.2  43.5 ± 6.3 (0.01 mg/mL)Example 1 8 1558.1 ± 145.7 867.9 ± 120.8 63.6 ± 7.0 (0.001 mg/mL)

Summary of Additional Studies Determination of Solubilities inFasted-State Simulated Colonic Fluid (FaSSCoF)

The solubilities of compounds of the invention in FaSSCoF at pH 6.5 aredetermined using a modification of a previously-reported procedure(Vertzoni, M., et al. Pharm. Res. 2010, 27, 2187-2196). In place of thebile salt extract employed in the original procedure (which extract isno longer available), the modified procedure uses a mixture of sodiumtaurochlorate (0.15 g), glycocholic acid (0.15 g), ursodeoxycholic acid(0.05 g), cholic acid (0.05 g), and glycodeoxycholic acid (0.05 g).These five bile acids are ground together with a mortar and pestle toproduce a fine white powder that is incorporated into the FaSSCoF, asoutlined below.

FaSSCoF Medium:

Tris(hydroxymethyl)aminomethane (Tris; 0.275 g) and maleic acid (0.44 g)are dissolved in water (35 mL) to give a solution whose pH is adjustedto 6.5 by treatment with 0.5M NaOH (ca. 12 mL). The solution is thenmade up to 50 mL with water. A portion of this Tris/maleate buffersolution (ca. 25 mL) is added to a 0.5 L round-bottomed flask, beforebeing treated with 0.00565 g of the bile acid mixture described above.Solutions of phosphatidylcholine (0.0111 g) in DCM (0.15 mL) andpalmitic acid (0.0013 g) in DCM (0.15 mL) are added, then the organicsolvent is evaporated off under reduced pressure at 40° C. until a clearsolution, with no perceptible DCM odour, is achieved. The volume of theevaporated solution is adjusted to 50 mL by addition of the remainder ofTris/maleate buffer, then BSA (0.115 g) is added, before being dissolvedby gentle agitation.

Solubility Determination:

Test compounds are suspended in the pH 6.5 FaSSCoF medium to give amaximum final concentration of 2-10 mg/mL. The suspensions areequilibrated at 25° C. for 24 h, before being filtered through a glassfibre C filter. The filtrates are then diluted as appropriate forinjection and quantification by HPLC with reference to a standard.Different volumes of the standard, diluted and undiluted samplesolutions are injected and the solubilities are calculated using thepeak areas determined by integration of the peak found at the sameretention time as the principal peak in the standard injection.

FaSSCoF solubilities are shown in Table 5 below, which reveals that manyof the compounds of the Examples exhibited solubilities in the FaSSCoFmedium at pH 6.5 of in excess of 0.01 mg/mL, while some displayedsolubilities greater than 0.1 mg/mL. With few exceptions, pH 6.5 FaSSCoFsolubilities were superior to those of Reference Compound A,3-((4-((4-(3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide{Fyfe, M. C. T., WO 2014/140582}.

TABLE 5 Solubilities measured for certain compounds of the Examples ofthe present invention in FaSSCoF at pH 6.5. Test Compound pH 6.5 FaSSCoFSolubility (mg/mL) Example No. Run 1 Run 2 Run 3 Run 4 ReferenceCompound A <0.001 <0.001 — —  1 0.016 0.018 0.010 0.011  1 (sodium salt)0.031 0.032 0.020 0.025  1 (hydrochloride salt) 0.016 0.015 — —  3 0.0060.006 — — 14 0.016 0.013 — — 15 0.010 0.010 — — 16 0.004 0.004 — — 17(b)0.015 0.015 — — 17(v) 0.008 0.008 — — 17(x) 0.015 0.009 — — 17(ae) 0.0110.012 — — 17(af) 0.010 0.010 — — 17(am) 0.010 0.012 — — 17(an) 0.0470.049 — — 17(ao) 0.009 0.009 — — 17(ap) <0.001 <0.001 — — 17(aq) <0.001<0.001 — — 17(ar) (hydrochloride salt) 0.204 0.198 — — 17(at) 0.0090.009 — — 17(au) 0.032 0.023 — — 17(ay) (hydrochloride salt) 0.029 0.028— — 17(az) 0.001 0.001 — — 17(bb) <0.001 <0.001 — — 17(bf) 0.013 0.015 —— 17(bg) 0.016 0.019 — — 17(bh) 0.016 0.019 — — 17(bj) (sodium salt)1.309 — — — 17(bk) (sodium salt) 0.042 0.037 — — 17(bl) 0.016 0.017 — —17(bm) 0.005 0.005 — — 17(bn) 0.008 0.006 — — 17(bo) 0.035 0.033 — —17(bp) 0.023 0.024 — — 17(bq) 0.009 0.009 — — 17(br) 0.009 0.008 — —17(bu) (dihydrochloride salt) 0.006 0.006 — — 17(bw) 0.002 0.003 — —17(bz) 0.021 0.026 0.014 0.019 17(ca) 0.002 0.002 — — 17(cd)(hydrochloride salt) 0.051 0.049 — — 17(cf) 0.003 0.001 — — 17(cg) 0.002— — — 17(ci) 0.006 0.006 — — 17(cl) 0.009 0.006 — — 17(cm) 0.008 0.009 —— 17(cn) 0.025 0.017 — — 17(co) 0.005 0.006 — — 19 (ammonium salt) 0.9460.881 — — 19 (sodium salt) >4.7 >4.7 — — 20 0.004 — — — 21 0.010 0.010 —— 22 0.017 0.025 0.013 0.009 23 0.008 0.008 — — 24 0.012 0.010 — — 260.011 0.011 — — 28 <0.001 <0.001 — — 29 0.011 0.009 — — 31 0.003 0.003 —— 33 0.005 0.005 — — 34 (hydrochloride salt) 0.001 0.001 — — 35 (sodiumsalt) >3.5 >4.2 — — 36 0.006 0.006 — — 37 0.025 0.024 0.007 0.006 380.014 0.012 — — 39 0.222 0.247 0.073 0.097 40 0.005 0.005 — — 41 0.0070.003 — — 42 0.007 0.009 — — 43 0.003 0.003 — — 44 (ammoniumsalt) >2.4 >2.4 — — 44 (sodium salt) >7.6 >5.5 — — 45 0.005 0.005 — — 47(sodium salt) >1.9 >2.0 — — 48 0.011 0.010 — — 68 (sodium salt) 0.0200.020 — — 70 (sodium salt) >2.8 >2.8 — —

Determination of Pharmacokinetic Parameters

Studies were conducted by Sai Life Sciences (Hinjewadi, Pune, India) toinvestigate the systemic pharmacokinetics and total colon tissuedistribution of compounds of the invention. In particular,pharmacokinetic studies were carried out in male C57BL/6 mice followinga single oral administration of the compound.

The data catalogued in Table 6 reveal that the compounds of theinvention achieve substantial colonic concentrations, while, incontrast, systemic plasma or blood exposures are very low or negligible.

TABLE 6 Mean plasma or blood concentrations (ng/mL) or total colonlevels (ng/g) obtained following oral administration of compounds of theinvention to mice at 5 mg/kg. Vehicle = 0.1% Tween 80 in 0.5%methylcellulose solution prepared in water. Cpd. Ex. No. Time (h) D M Mx0.5 1 2 4 6 8 12 24  1 1 Pl 44.9 49.2 13.0 5.2 1.9 0.6 5.3 0.0 (Na salt)TC 4.3 9.3 52.4 10,403 4,049 12,898 535 41.4 19 19 Bd 0.0 0.0 0.0 0.00.0 0.0 0.0 0.0 (Na salt) TC 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 16 Bd 1.31.4 0.6 0.0 0.0 0.2 0.0 0.0 TC 9.5 110 2,402 3,354 3,325 3,423 5,086 0.044 44 Pl 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (NH₄ ⁺ salt) TC 0.0 0.0 2,3281,751 450 915 180 0.0 47 47 Bd 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (Na salt)TC 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 36 Bd 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0TC 37.8 95.1 643 798 380 1,068 139 0.0 Key to Table 6 D = compoundadministered (dosed) M = compound measured Mx = matrix Pl = plasma Bd =blood TC = total colonhERG Inhibition Studies

Compounds of the invention were tested for inhibition of the human ethera go-go (hERG) channel using IonWorks™ patch clamp electrophysiology atEssen Bioscience (Welwyn Garden City, England).

TABLE 7 hERG inhibition data for compounds of the invention % Inhibitionat Top Top Example IC₅₀ (μM) Concentration Concentration  1 >3.3 −4  3μM  2 >3.3 −2  3 μM 17(j) >3.3 7  3 μM 22 >3.7 13 3.7 μM  36 >11.0 24 11μM 41 >11.0 7 11 μM 43 >11.0 13 11 μM 44 >11.0 18 11 μM 47 >11.0 19 11μM 48 >11.0 −6 11 μM

Acute Eye Irritation/Corrosion Study

The objective of the acute eye irritation/corrosion study was to assessthe possible irritation or corrosion potential of the compound ofExample 1 at two selected dose levels (0.1 and 1.0 mg/mL), in comparisonto vehicle (4% w/v polyoxyethylene 40 stearate/4% w/v mannitol/phosphatebuffer (pH 7.4) solution), after one treatment day (Phase 1) or threeconsecutive treatment days (Phase 2) with four daily administrations(4-hours apart) by the ocular route (bi-lateral instillations of 40μL/eye/instillation) in the eyes of albino New Zealand White rabbits(13-15 weeks at initiation of dosing; 2 males and 2 females per dosegroup).

During the study, there were no unscheduled deaths, nor testitem-related clinical signs. Furthermore, there were no effects on bodyweight, nor on food consumption.

In Phase 1, ocular reactions were limited mainly to conjunctival redness(grade 1 or 2) and occasionally to chemosis (grade 1) and discharge(grade 1), in all groups, after instillation of the vehicle or of thetest item, Example 1, formulation at any dose levels. These scores wereslight to moderate. There were no differences in the frequency, severityand incidence between the Example 1-treated animals and the vehiclecontrols. The conjunctival redness was the most frequent reaction, andwas yet present (at grade 1) before the start of dosing. This localreaction is known to occur spontaneously in the albino rabbit duringocular studies and is related to the numerous ocular examinationsundergone on the animals. Chemosis and discharge were sporadicallyobserved in all groups after the first instillation and over the 3-dayobservation period thereafter. In addition, congestion of the iris wasoccasionally and unilaterally observed in the eyes of the two high dosegroup rabbits (1 mg/mL) and one vehicle group female. The Draizeexamination confirmed the integrity of the cornea after a singletreatment day and the photomotor reflex was normal for all animals onall occasions. In summary, the local tolerability of the formulationswas thus considered to be acceptable after a single dosing day. Similarlocal reactions were observed after instillation of the vehicle orformulations containing the compound of Example 1, indicative of amoderate vehicle-related effect on the ocular tolerance.

In Phase 2, the main ocular reactions were limited to conjunctivalredness (grade 1) in all groups after instillation of the vehicle or ofthe test item formulations at any dose levels. This score was slight andwas noted without any meaningful difference in the incidence andfrequency between groups throughout the 3-day treatment period. Theseverity was occasionally higher (grade 2) in the vehicle group than inthe test item-treated groups. This conjunctival redness was persistentand was still observed before the first instillation on the followingday. In addition, congestion of the iris was occasionally observed inthe eyes of the two high dose group rabbits and one vehicle groupfemale. No discharge was observed in any animals at all occasions. TheDraize examination confirmed the integrity of the cornea during the3-day treatment period. The photomotor reflex was normal for all animalson all occasions. In summary, the local tolerability of the formulationswas thus considered to be acceptable without any aggravation for the 3treatment days. Similar local reactions were observed after instillationof the vehicle alone or formulations containing the compound of Example1, indicative of the moderate vehicle-related effect on the oculartolerance.

Mutagenicity Assessment (Bacterial Reverse Mutation Screen)

Studies were conducted by Sequani (Ledbury, Herefordshire, UK) to assessthe compounds of Examples 1 and 44 in vitro for their ability to inducemutations in four histidine dependent auxotrophic mutants of Salmonellatyphimurium, strains TA1535, TA1537, TA98 and TA100 and one tryptophandependent auxotrophic mutant of Escherichia coli, WP2 uvrA.

The mutation screen was conducted using the plate incorporation methodand was performed in both the presence and absence of S-9 mix (a liverpost-mitochondrial fraction derived from the livers of Aroclor 1254treated rats). The bacteria were exposed to the compound of Example 1 orExample 44 dissolved in dimethylsulphoxide, which solvent was also usedas the negative control. The positive Control chemicals were SodiumAzide (TA1535 and TA100), 9-Aminoacridine (TA1537), 2-Nitrofluorene(TA98) and 4-Nitroquinoline-N-Oxide (WP2 uvrA) in the absence of S-9 mixand 2-Aminoanthracene (all strains) in the presence of S-9 mix.

The doses of the compound of Example 1 used in the mutation test underplate incorporation conditions were 15, 50, 150, 500 or 1500 μg/plate inall strains in the presence and absence of S-9 mix.

The doses of the compound of Example 44 used in the mutation test underplate incorporation conditions were 50, 150, 500, 1500 or 5000 μg/platein all strains in the presence and absence of S-9 mix.

The compound of Example 1 was analysed up to the limit of solubility of1500 μg/plate in all strains in the presence and absence of S-9 mix,under plate incorporation conditions. The compound of Example 44 wasanalysed up to the limit of solubility of 5000 μg/plate in all strainsin the presence and absence of S-9 mix, under plate incorporationconditions.

Precipitation was observed:

-   -   for the compound of Example 1, at 500 μg/plate in TA1537 and        TA98 in the presence of S-9 mix, and at 1500 μg/plate in all        strains in the presence and absence of S-9 mix; and    -   for the compound of Example 44, at 5000 μg/plate in TA1535 in        the presence and absence of S-9 mix, and in TA100 in the absence        of S-9 mix

There was also a reduction in the mean colony count:

-   -   for the compound of Example 1, at 500 μg/plate and 1500 μg/plate        in TA98 and at 1500 μg/plate in TA1535, in the presence of S-9        mix; and    -   for the compound of Example 44, at 1500 μg/plate in TA98 and        5000 μg/plate in TA98 and WP2 uvrA, in the absence of S-9 mix,        and at 5000 μg/plate in TA1535, TA1537, TA98 and TA100 in the        presence of S-9 mix,        indicating toxicity of the test items to the bacteria.

There were no dose-related or statistically significant increases inrevertant numbers observed in any strain at any dose level of thecompound of Example 1 or the compound of Example 44, in the presence orabsence of S-9 mix, under plate incorporation conditions. This indicatesthe absence of any mutagenic effects for the compounds of Examples 1 and44 under the conditions of the test.

Hydrolytic Stability Study

Chemical stability of compounds of the invention was assessed in amixture of DMSO and water (3:1) at a test compound concentration of 1mg/mL.

General HPLC Procedure

-   -   Agilent, Waters X-Select C18, 2.5 μm, 4.6×30 mm column, 4 min        method, 5-95% MeCN/water (0.1% formic acid). Flow rate 2.5        mL/min. Column Oven Temperature 40° C. Detection 254 nm.

Sample Preparation

-   -   A 1.0 mg sample of test compound was dissolved in 750 μL of        DMSO. Water (250 μL) was added slowly, ensuring no precipitation        occurred.

Recording Stability

-   -   A 50 μL aliquot of the test solution was removed and analysed in        duplicate by 5 μL HPLC injections. The peak area for the test        compound was recorded following manual integration of the        corresponding UV trace.    -   The test solution was heated to 60° C., with stirring, and 50 μL        aliquots removed for HPLC analysis at 5 and 24 h timepoints. In        all cases, 5 μL injections were used and the samples analysed in        duplicate.    -   The peak areas for the test compounds were recorded at both        subsequent timepoints and the % decomposition calculated from        the % change in peak area over time.    -   Reference Compound B        (3-ethynyl-5-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;        Cariou, C. A. M., et al, WO 2014/027209) was included in each        stability study as a control to validate the study. In contrast        to the compounds of the present invention, this Reference        Compound underwent substantial decomposition under the        conditions of the experiment.

The results of the study are reported in the table below.

Test Compound Time (min) % Parent Remaining Reference Compound B 0 100297 79 1429 18 Example 44 0 100 307 102 1439 98 Example 47 0 100 317 1041450 89

Stability of Pharmaceutical Formulations

20 mL of 1 mg/mL stock solutions were prepared, in duplicate, of thesodium (Na) and hydrochloride (HCl) salts of the compound of Example 1as follows: The appropriate quantities of each salt were mixed with 10mM pH 7.2 phosphate buffer containing 4.5% mannitol and 3% polyoxyl 40stearate. The samples were sonicated to achieve clear solutions havingthe following properties: Osmolality (mOsm/kg): 310 (Na), 314 (HCl); pH:7.00 (Na), 7.05 (HCl). 0.5 mL of the stock solutions were diluted to 1mL with 20% DMSO in water & injected for purity analysis by HPLC. Theremaining stock solutions were then split into aliquots of 0.5 mL inHPLC vials, and stored at various conditions in duplicate. Samples werestored at 5 and 25° C., before being analysed by HPLC at 1, 2 and 4weeks. Separate samples were stored at 40° C. and analysed at 4 weeks.The analysis shown in the Table below reveals that the Compound ofExample 1 is stable in solution at 5° C.

Original Purity Purity (%) at week n Test substance Sample (%) Temp (°C.) n = 1 n = 2 n = 4 Example 1, 1 98.6 5 98.2 98.4 98.3 sodium salt 2598.4 98.1 97.6 40 — — 76.0 2 98.5 5 98.4 98.5 98.4 25 98.5 98.1 97.6 40— — 73.7 Example 1, 1 98.1 5 98.2 98.1 97.9 hydrochloride salt 25 98.097.7 97.2 40 — — 79.2 2 98.1 5 98.2 98.0 98.0 25 98.0 97.6 97.4 40 — —80.4

Abbreviations

-   -   AcOH glacial acetic acid    -   aq aqueous    -   5-ASA 5-aminosalicylic acid    -   ATP adenosine-5′-triphosphate    -   BALF bronchoalveolar lavage fluid    -   BID bis in die (twice-daily)    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate    -   br broad    -   BrdU 5-bromo-2′-deoxyuridine    -   BSA bovine serum albumin    -   CatCart® catalytic cartridge    -   CDI 1,1-carbonyl-diimidazole    -   COPD chronic obstructive pulmonary disease    -   d doublet    -   dba dibenzylideneacetone    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC dicyclohexylcarbodiimide    -   DCM dichloromethane    -   DIAD diisopropyl azodicarboxylate    -   DIPEA diisopropylethylamine    -   DMAP 4-dimethylaminopyridine    -   DMEM Dulbecco's modified eagle medium    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   DPPA diphenylphosphoryl azide    -   d-U937 cells PMA differentiated U-937 cells    -   EDTA ethylenediaminetetraacetic acid    -   ELISA enzyme-linked immunosorbent assay    -   (ES⁻) electrospray ionization, negative mode    -   (ES⁺) electrospray ionization, positive mode    -   Et ethyl    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FACS fluorescence-activated cell sorting    -   FBS foetal bovine serum    -   FCS foetal calf serum    -   fMLP formyl-methionyl-leucyl-phenylalanine    -   FRET fluorescence resonance energy transfer    -   GSK3α glycogen synthase kinase 3α    -   HBEC primary human bronchial epithelial cells    -   HBSS Hank's balanced salt solution    -   HPLC high performance liquid chromatography    -   HPMC hydroxypropylmethylcellulose    -   h or hr hour(s)    -   HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluorophosphate    -   HOAt 1-hydroxy-7-azabenzotriazole    -   HOBt hydroxybenzotriazole    -   HRP horseradish peroxidise    -   HRV human rhinovirus    -   ICAM-1 inter-cellular adhesion molecule 1    -   IFNγ interferon-γ    -   IL interleukin    -   iPrOAc isopropyl acetate    -   JNK c-Jun N-terminal kinase    -   LC liquid chromatography    -   Lck lymphocyte-specific protein tyrosine kinase    -   LPS lipopolysaccharide    -   m multiplet    -   (M+H)⁺ protonated molecular ion    -   MAPK mitogen-activated protein kinase    -   MAPKAP-K2 mitogen-activated protein kinase-activated protein        kinase-2    -   mCPBA meta-chloroperbenzoic acid    -   Me methyl    -   MeCN acetonitrile    -   MeOH methanol    -   MHz megahertz    -   min or mins minute(s)    -   MMAD mass median aerodynamic diameter    -   MOI multiplicity of infection    -   MPO myeloperoxidase    -   MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide    -   MS mass spectrometry    -   m/z mass-to-charge ratio    -   NMP N-methyl pyrrolidinone    -   NMR nuclear magnetic resonance (spectroscopy)    -   OD optical density    -   PBMC peripheral blood mononuclear cell    -   PBS phosphate buffered saline    -   Ph phenyl    -   PHA phytohaemagglutinin    -   PMA phorbol myristate acetate    -   pTSA 4-methylbenzenesulfonic acid (para-toluenesulfonic acid)    -   PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   q quartet    -   rt or RT room temperature    -   RP HPLC reverse phase high performance liquid chromatography    -   rpm revolutions per minute    -   RPMI Roswell Park Memorial Institute    -   RSV respiratory syncytial virus    -   s singlet    -   sat or satd saturated    -   SCID severe combined immunodeficiency    -   SCX solid supported cation exchange (resin)    -   SDS sodium dodecyl sulfate    -   S_(N)Ar nucleophilic aromatic substitution    -   Syk Spleen tyrosine kinase    -   t triplet    -   T3P 1-propanephosphonic acid cyclic anhydride    -   TBAF tetrabutylammonium fluoride    -   TBDMS tert-butyldimethylsilyl    -   TCID₅₀ 50% tissue culture infectious dose    -   TEA triethylamine    -   THF tetrahydrofuran    -   TFA trifluoroacetic acid    -   TGFβ transforming growth factor beta    -   TIPS triisopropylsilyl    -   TMB 3,3′,5,5′-tetramethylbenzidine    -   TMS-Cl trimethylsilyl chloride    -   TNFα tumor necrosis factor alpha

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

What is claimed is:
 1. A compound of: (a) formula III,

or a salt or protected derivative of said compound of formula III,wherein Z² represents a structural fragment of formula V:

wherein R² and R³, together with the C-atoms to which they are attached,form a fused phenyl or pyridyl ring, which latter two rings areoptionally substituted by one or more substituents selected from C₁₋₃alkyl, C₁₋₃ haloalkyl, cyano and halo, or one of R² and R³ represents H,halo, cyano, C₁₋₃ alkyl or C₁₋₃ haloalkyl and the other independentlyrepresents halo, cyano, C₁₋₃ alkyl or C₁₋₃ haloalkyl, or R² and R³together combine to form C₃₋₅ alkylene or C₃₋₅ alkenylene, which lattertwo groups are optionally substituted by one or more substituentsselected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano and halo; X¹ representsN or CH; L represents a direct bond or C₁₋₂ alkylene; X² representsCR^(Z) or N; X³ represents CR^(5b) or N; R^(Z) represents H, halo,cyano, hydroxy, C₁₋₃ alkyl or C₁₋₃ alkoxy, which latter two groups areoptionally substituted by one or more halo atoms; R⁴ represents-Q¹-[C(R^(6c))(R^(6d))—(CH₂)₀₋₁CH₂—Z]₁₋₁₂—CH₂(CH₂)₀₋₁CH₂—R^(6a),-Q²-C(R^(6c))(R^(6d))—[C₁₋₅ alkylene]-R^(6a), which C₁₋₅ alkylene groupis optionally substituted by oxo and/or by one or more R^(6e), -Q³-[C₁₋₄alkylene]₀₋₁-Het^(x1), which C₁₋₄ alkylene group is optionallysubstituted by oxo and/or by one or more R^(6e) and which Het^(x1) groupis optionally substituted by one or more substituents selected fromhalo, hydroxy, oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₄alkyl, the C₁₋₄ alkyl part of which latter group is optionallysubstituted by one or more R^(6e), -Q²²-[C₁₋₄ alkylene]₀₋₁-phenyl, whichC₁₋₄ alkylene group is optionally substituted by oxo and/or by one ormore R^(6e), and which phenyl group is substituted by —[C(O)]₀₋₁—C₁₋₄alkyl, the C₁₋₄ alkyl part of which latter group is optionallysubstituted by one or more R^(6e), and which phenyl group is optionallyfurther substituted by one or more substituents selected from halo,hydroxy, oxo, C₃₋₆ cycloalkyl and C₁₋₃ alkoxy, —S(O)_(p)R^(6b), —[C₁₋₄alkylene]₀₋₁-CO₂H, Het^(x2) which Het^(x2) group is optionallysubstituted by one or more substituents selected from halo, hydroxy,oxo, C₁₋₃ alkyl and C₁₋₃ alkoxy, —COR^(6b), —CH₂OH, —CH₂OP(O)(OH)₂ or-Q⁴-P(O)(OR⁹)(R⁷); Z represents, independently upon each occurrence, O,C(O)N(R⁸) or N(R⁸)C(O); R^(5a) and R^(5b) independently represent C₁₋₃alkoxy or C₁₋₃ alkyl, which latter two groups are optionally substitutedby one or more halo atoms, or R^(5a) and R^(5b) independently represent—N(R^(e))(R^(f)), C₂₋₃ alkynyl, H, cyano, —C(O)NH₂, hydroxy, halo or—S(O)₀₋₂—C₁₋₃ alkyl; R^(6a) represents OR^(7a), —S(O)₀₋₂R^(7aa),N(R^(7b))R^(7c) or CO₂H; R^(6b) represents C₁₋₈ alkyl, C₃₋₈ cycloalkyl,phenyl, Het¹ or Het², which latter five groups are optionallysubstituted by one or more substituents selected from halo, hydroxy,—OP(O)(OH)₂, C₁₋₃ alkyl, C₁₋₃ alkoxy, —C₁₋₃ alkylene-R^(6e) and CO₂H, orR^(6b) represents —C₁₋₄ alkylene-Het³, which Het³ group is optionallysubstituted by one or more substituents selected from halo, hydroxy,oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, which C₁₋₃alkyl group is optionally substituted by one or more R^(6e), or, when pis 1 or 2, R^(6b) may alternatively represent OH, or, when p is 2,R^(6b) may alternatively represent —N(R^(7b))R^(7c) or—N(R^(7b))—C(O)—R^(7c); R^(6e) represents, independently upon eachoccurrence, halo, hydroxy, —OP(O)(OH)₂, C₁₋₃ alkoxy, —N(R^(g))(R^(h)) or—CO₂H; R^(7a) to R^(7c) independently represent H or C₁₋₄ alkyloptionally substituted by one or more halo atoms or by —CO₂H, or R^(7a)represents P(O)(OH)₂ or Het³, which latter group is optionallysubstituted by one or more substituents selected from halo, hydroxy,oxo, C₃₋₆ cycloalkyl, C₁₋₃ alkoxy and —[C(O)]₀₋₁—C₁₋₃ alkyl, which C₁₋₃alkyl group is optionally substituted by one or more R^(6e), or R^(7b)and/or R^(7c) represents —[C_(a) alkylene]-[C_(b) alkylene]-OR^(7d), orR^(7b) and R^(7c) together with the N-atom to which they are attached,form a 4- to 7-membered heterocyclic group that is fully saturated,partially unsaturated or fully aromatic and which heterocyclic groupcontains one N atom (the atom to which R^(7b) and R^(7c) are attached)and, optionally, one or more further heteroatoms selected from O, S andN, and which heterocyclic group is optionally substituted by one or moresubstituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl, C₁₋₄ alkoxyand C₁₋₄ hydroxyalkyl; a and b independently represent an integerselected from 1, 2 and 3, wherein the sum of a and b is 2, 3 or 4;R^(7d) represents H or C₁₋₄ alkyl optionally substituted by one or morehalo atoms; R^(7aa) represents —C(R^(7d))(R^(7e))—C₁₋₃ alkylene-OH orC₁₋₄ alkyl optionally substituted by one or more halo atoms or by —CO₂H;Q¹, Q², Q²² and Q³ independently represent —C(O)N(R⁸)—, —O— or—S(O)₂N(R⁸)—, or Q¹, Q² and Q²² independently represent S(O)_(q); Q⁴represents a direct bond or C₁₋₃ alkylene; n, m, p and q independentlyrepresent 0, 1 or 2; R^(6c), R^(6d), R^(e), R^(f), R^(g), R^(h) and R⁸independently represent H or methyl, or R^(6c) and R^(6d) independentlyrepresent hydroxymethyl; R⁷ represents H, hydroxy, C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₇ cycloalkyl or phenyl, which latter four groups areoptionally substituted by one or more substituents selected from halo,OH, C₁₋₃ alkyl and C₁₋₃ alkoxy; R⁹ represents H or C₁₋₄ alkyl, whichlatter group is optionally substituted by one or more halo atoms or byphenyl, which phenyl group is optionally substituted by one or moresubstituents selected from halo, OH, C₁₋₃ alkyl and C₁₋₃ alkoxy;Het^(x1) and Het^(x2) independently represent Het^(1a) or Het³; Het¹ andHet^(1a) represent, independently upon each occurrence, a 5- or6-membered heterocyclic group that is fully aromatic, which groupcontains one or more heteroatoms selected from N, O and S; and Het² andHet³ represent, independently upon each occurrence, a 4- to 9-memberedheterocyclic group that is fully saturated or partially unsaturated, andis monocyclic or is fused or bridged bicyclic, which group contains oneor more heteroatoms selected from N, O and S; or (b) formula VIIa:

or a salt or protected derivative of said compound of formula VIIa,wherein Q^(x) represents —[C₁₋₄ alkylene]₀₋₁-C(O)O—C₁₋₄ alkyl; R^(1A)represents C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, whichlatter four groups are optionally substituted by one or moresubstituents selected from C₁₋₂ alkyl, halo, hydroxy, —OP(O)(OH)₂ andC₁₋₂ alkoxy, H, halo, cyano, phenyl or Het¹, which latter two groups areoptionally substituted with one or more substituents selected from C₁₋₂alkyl and C₁₋₂ alkoxy, or R^(1A) and R^(1B) together represent astructural fragment selected from the following

wherein the wavy lines represent the points of attachment to the phenylring; A represents O, S or N(R^(A2)); R^(A1) represents H, C₁₋₄ alkyl orhydroxy; R^(A2) represents H or C₁₋₄ alkyl; R^(1B) represents—NR^(X)S(O)₂R^(Y1), —C(O)NR^(X)R^(Y), H, halo, cyano, —C₁₋₄ alkylene-CN,—C₁₋₄ alkylene-OH, —NR^(X)R^(X1), —C(O)OR^(X), —S(O)₂NR^(X)R^(Y),—NR^(X)C(O)R^(Y), —NR^(X2)S(O)₂NR^(X)R^(Y), —NR^(X)P(O)R^(Y1)R^(Y2),—NR^(X)C(O)OR^(Y1) or Het¹ optionally substituted with one or moresubstituents selected from halo, hydroxy, C₁₋₂ alkyl and C₁₋₂ alkoxy;R^(X) and R^(X1) independently represent H or C₁₋₆ alkyl optionallysubstituted by one or more substituents selected from halo, hydroxy,—OP(O)(OH)₂ and C₁₋₂ alkoxy, or R^(X) and R^(X1) together represent C₃₋₆n-alkylene or C₄₋₅ n-alkylene interrupted between C2 and C3 by —O— or—N(R^(X2))—, or R^(X1) represents Het¹ optionally substituted with oneor more substituents selected from halo, hydroxy, C₁₋₂ alkyl and C₁₋₂alkoxy; R^(Y), R^(Y1) and R^(Y2) independently represent C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, benzyl, Het¹ or Het², which latter six groupsare optionally substituted by one or more substituents selected fromC₁₋₂ alkyl, halo, hydroxy, —OP(O)(OH)₂, C₁₋₂ alkoxy, C(O)OH, C(O)O—(C₁₋₄alkyl) and —N(R^(a))(R^(b)), and/or which Het² group is substituted withone or more oxo groups, or R^(Y) represents H, or R^(X) and R^(Y)together represent C₃₋₆ n-alkylene or C₄₋₅ n-alkylene interruptedbetween C2 and C3 by —O—, —S(O)_(n)— or —N(R^(X2))—; R^(a) and R^(b)independently represent H, methyl or —C(R^(c))(R^(d))—C₁₋₃ alkyl, theC₁₋₃ alkyl portion of which latter group is optionally substituted byone or more hydroxy substituents, or R^(a) and R^(b) together representC₃₋₆ n-alkylene or C₄₋₅ n-alkylene interrupted between C2 and C3 by —O—,—S(O)_(m)— or —N(R^(X2))—; R^(c) and R^(d) independently represent H ormethyl; each R^(X2) independently represents H or C₁₋₄ alkyl; R^(1C) andR^(1E) independently represent H, halo, cyano or methyl; provided thatat least one of R^(1A), R^(1B), R^(1C) and R^(1E) is other than H;R^(1D) represents trimethylsilyl, C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, phenyl, Het¹ or Het², which latter sevengroups are optionally substituted by one or more substituents selectedfrom C₁₋₂ alkyl, halo, cyano, hydroxy, —OP(O)(OH)₂ and C₁₋₂ alkoxy; R²and R³, together with the C-atoms to which they are attached, form afused phenyl or pyridyl ring, which latter two rings are optionallysubstituted by one or more substituents selected from C₁₋₃ alkyl, C₁₋₃haloalkyl, cyano and halo, or one of R² and R³ represents H, halo,cyano, C₁₋₃ alkyl or C₁₋₃ haloalkyl and the other independentlyrepresents halo, cyano, C₁₋₃ alkyl or C₁₋₃ haloalkyl, or R² and R³together combine to form C₃₋₅ alkylene or C₃₋₅ alkenylene, which lattertwo groups are optionally substituted by one or more substituentsselected from C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano and halo; X¹ representsN or CH; L represents a direct bond or C₁₋₂ alkylene; X² representsCR^(Z) or N; X³ represents CR^(5b) or N; R^(Z) represents H, halo,cyano, hydroxy, C₁₋₃ alkyl or C₁₋₃ alkoxy, which latter two groups areoptionally substituted by one or more halo atoms; Het¹ represents,independently upon each occurrence, a 5- or 6-membered heterocyclicgroup that is fully aromatic, which group contains one or moreheteroatoms selected from N, O and S; and Het² represents, independentlyupon each occurrence, a 4- to 9-membered heterocyclic group that isfully saturated or partially unsaturated, and is monocyclic or is fusedor bridged bicyclic, which group contains one or more heteroatomsselected from N, O and S.
 2. A compound of: (a) formula III, or a saltor protected derivative thereof, as claimed in claim 24, wherein saidcompound or protected derivative is methyl4-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoateor methyl4-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate;or (b) formula VIIa, or a salt or protected derivative thereof, asclaimed in claim 24, wherein said compound is methyl4-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)-phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-2-methoxybenzoate.